Oxidative Stress in The Brain Novel Cellular Targets That Govern 2005

Progress in Neurobiology 75 (2005) 207246 www.elsevier.
com/locate/pneurobio
Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease
Zhao Zhong Chong a, Faqi Li a, Kenneth Maiese a,b,c,*
b a Division of Cellular and Molecular Cerebral Ischemia, Wayne State University School of Medicine, Detroit, MI 48201, USA Department of Neurology and Anatomy & Cell Biology, Center for Molecular Medicine and Genetics, Institute of Environmental Health Sciences, Wayne State University School of Medicine, 8C-1 UHC, 4201 St. Antoine, Detroit, MI 48201, USA c Center for Molecular Medicine and Genetics, Institute of Environmental Health Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA
Received 29 July 2004; accepted 16 February 2005
Abstract Despite our present knowledge of some of the cellular pathways that modulate central nervous system injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. The cellular mechanisms that precipitate these diseases are more involved than initially believed. As a result, identication of novel therapeutic targets for the treatment of cellular injury would be extremely benecial to reduce or eliminate disability from nervous system disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we discuss novel pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inammation and vascular occlusion. Current work has identied exciting pathways, such as the Wnt pathway and the serinethreonine kinase Akt, as central modulators that oversee cellular apoptosis and their downstream substrates that include Forkhead transcription factors, glycogen synthase kinase-3b, mitochondrial dysfunction, Bad, and Bcl-xL. Other closely integrated pathways control microglial activation, release of inammatory cytokines, and caspase and calpain activation. New therapeutic avenues that are just open to exploration, such as with brain temperature regulation, nicotinamide adenine dinucleotide modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat a variety of disorders that include stroke, Alzheimers disease, and traumatic brain injury. # 2005 Elsevier Ltd. All rights reserved.
Abbreviations: Ab, b-amyloid; AD, Alzheimers disease; AIF, apoptosis-inducing factor; ALS, amyotrophic lateral sclerosis; Apaf-1, apoptotic proteaseactivating factor; APC, adenomatous polyposis coli; APP, amyloid precursor protein; BrdU, bromodeoxyuridine; CARD, caspase recruitment domain; CDK, cyclin-dependent kinase; CNS, central nervous system; CPCR, G protein-coupled receptor; CREB, cAMP-response element-binding protein; CTMP, carboxyterminal modulator protein; EC, endothelial cell; eIF2B, the translation initiation factor 2B; EPO, erythropoietin; FADD, Fas-associated protein with death domain; FLIP, Fas-associated death domain-like interleukins 1b converting enzyme-like inhibitory protein; FRAT1, frequently rearranged in advanced T-cell lymphoma type 1; GSK-3b, glycogen synthase kinase-b; HD, Huntingtons disease; 4-HNE, 4-hydroxynonenal; IAP, inhibitor of apoptosis protein; IKK, IkB kinase; JNK, c-Jun-amino terminal kinases; Lef, lymphocyte enhancer factor; LPR, lipoprotein related protein; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NF-kB, nuclear factor-kB; NO, nitric oxide; 6-OHDA, 6-hydroxydopamine; OHdG, 8-hydroxy-2-deoxyguanosine; OGD, oxygen-glucose deprivation; PARP, poly(ADP-ribose) polymerase; PCD, programmed cell death; PCNA, proliferating cell nuclear antigen; PD, Parkinsons disease; PDK1, phosphoinositide-dependent kinase-1; PI 3-K, phosphoinositide 3 kinase; PIP2, phosphatidylinositol 3,4-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKB, protein kinase B; PKC, protein kinase C; PP2A, protein phosphatase 2A; PS, phosphatidylserine; PS1, presenilin 1; PTEN, the phosphatase and tensin homolog deleted from chromosome 10; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; SN, substantia nigra; SOD, superoxide dismutase; Tcf, T cell factor; TCL1, the T cell leukemia/lymphoma 1; TNF, tumor necrosis factor; WISP-1, Wnt-1 induced secreted preotein-1 * Corresponding author at: Department of Neurology, Department of Anatomy & Cell Biology, Center for Molecular Medicine and Genetics, Institute of Environmental Health Sciences, Wayne State University School of Medicine, 8C-1 UHC, 4201 St. Antoine, Detroit, MI 48201, USA. Tel.: +1 313 966 0833; fax: +1 313 966 0486. E-mail address: kmaiese@med.wayne.edu (K. Maiese). 0301-0082/$ see front matter # 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2005.02.004
208
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The population at risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Elucidating novel targets within the cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. The biology of oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative stress and neurodegenerative disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Acute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Chronic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early and late apoptotic programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microglial activation and inammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Attempted cell cycle induction in post-mitotic cells . . . . . . . . . . . . . . . . . . . . . . . . . . . Induction of the Wnt pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Akt as an essential regulatory element . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Activation and expression of Akt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Akt as a modulator apoptotic injury and inammation during ROS exposure. . . . . 7.3. Akt can provide the stimulus for altering the course of neurodegenerative disease . Downstream cellular targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. The Forkhead transcription factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. GSK-3b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Bad, Bcl-xL, and NF-kB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. Mitochondrial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5. Caspases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6. Calpains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 208 208 209 210 210 210 212 213 214 215 216 216 218 219 220 220 222 223 224 227 229 230 233 233
2.
3. 4. 5. 6. 7.
8.
9.
1. Introduction 1.1. The population at risk At present, over 23 million people in the United States suffer from central nervous system (CNS) disorders. Globally, this number reaches a level of 368 million people. These disorders predominantly consist of neurodegenerative diseases that include presenile dementia, Alzheimers disease (AD), and Parkinsons disease (PD). Intimately linked to the development of CNS degeneration are also a variety of injuries associated with traumatic brain injury (TBI). For example, both penetrating head injuries and blast injuries without direct head trauma have been shown to result in subsequent neurotrauma as a result of potential elevations in nervous system oxidative stress and free radical levels (Cernak et al., 2000). In addition to direct head trauma, diffuse neuronal degeneration can ensue as a result of an increased load of kinetic energy from the original insult (Carey et al., 1984). Furthermore, tangential cranial injuries are susceptible to acute ischemic neuronal injury with intracerebral hemorrhage (Elron et al., 1998). Finally, environmental toxin exposure also may foster oxidative neuronal and vascular damage (Miller et al., 2002) (Table 1). In the general population, the cost of physician services, hospital and nursing home care, and medications continues to rise dramatically. In addition, these medical costs for neurodegenerative disease parallel a progressive loss of economic productivity with rising morbidity and mortality,
ultimately resulting in an annual decit to the economy that is greater than $ 380 billion. Interestingly, the most signicant portion of this economic loss is composed of only a few neurodegenerative disease entities, such as ischemic disease and AD. The annual cost per patient with AD is estimated at $ 174,000 with an annual population aggregate cost of $ 100 billion (McCormick et al., 2001; Mendiondo et al., 2001). 1.2. Elucidating novel targets within the cell Despite our present knowledge of some of the cellular pathways that modulate CNS injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. As a result, identication of novel therapeutic targets for the treatment of neuronal injury would be extremely benecial to reduce or eliminate disability from CNS disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we describe the unique capacity of intrinsic cellular mechanisms that may offer novel therapy for a variety of acute and chronic disorders in both neuronal and vascular systems. Oxidative stress leads to apoptotic injury that involves early loss of cellular membrane asymmetry as well as the eventual destruction of genomic DNA. These dynamic stages of apoptosis can be associated with an ill-fated attempt to enter the cell cycle, particularly in post-mitotic neurons. Subsequent cellular pathways can originate from the proto-oncogene Wnt and the serine
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Table 1 Oxidative stress in central nervous system disorders Diseases Acute Cerebral ischemia/ reperfusion Traumatic brain injury Chronic Alzheimers disease Demonstration Superoxide radical and peroxynitrite increased on microvessels; impaired mitochondrial function; protection with reactive oxygen species reduction Reactive oxygen species increased; lipid peroxidation and protein oxidation increased; antioxidant reserve decreased Selected references Bazan et al. (2002); Yamato et al. (2003); Gursoy-Ozdemir et al. (2004) and Demougeot et al. (2004)
209
Awasthi et al. (1997); Tyurin et al. (2000); Marklund et al. (2001) and Bayir et al. (2002)
Oxidation of lipids, DNA, and proteins increased; induction of reactive Behl et al. (1994); Montine et al. (1999); oxygen species by amyloid-b; metal ion reduction in senile plaques; McGrath et al. (2001); Monji et al. (2001) formation of ion-permeable channels and Boland and Campbell (2003) Oxidation of lipid, DNA, and proteins increased in substantia nigra Oxidative DNA damage increased in the basal ganglia; reactive oxygen species present Alam et al. (1997); Groc et al. (2001); Zigmond et al. (2002) and Basso et al. (2004) Browne et al. (1997); Bogdanov et al. (2001) and Perez-Severiano et al. (2004) Rosen et al. (1993); Liu et al. (1999) and Jung et al. (2001)
Parkinsons disease Huntingtons disease
Amyotrophic lateral sclerosis Reactive oxygen species increased; oxidation of lipids, DNA, and proteins increased; mutant in copper zinc superoxide dismutase; protection with reactive oxygen species reduction
threonine kinase Akt and involve mechanisms linked to inammatory activation of microglia, Forkhead transcription factors, glycogen synthase kinase-3b activation, loss of mitochondrial membrane permeability, and the eventual induction of caspases and calpains. Understanding these processes may ultimately serve to elucidate robust therapeutic strategies linked to brain temperature, cellular metabolism, genomic DNA repair, metabotropic glutamate modulation, and cytokine regulation that allow future clinical strategies to mature from bench side prediction to daily practice. 1.3. The biology of oxidative stress Oxidative stress occurs when oxygen free radicals are generated in excess through the reduction of oxygen. Reactive oxygen species (ROS) consist of oxygen free radicals and associated entities that include superoxide free radicals, hydrogen peroxide, singlet oxygen, nitric oxide (NO), and peroxynitrite. Several of these species are produced at low levels during normal physiological conditions and are scavenged by endogenous antioxidant systems that include superoxide dismutase (SOD), glutathione peroxidase, catalase, and small molecule substances such as Vitamins C and E. Superoxide radical is the most commonly occurring oxygen free radical that produces hydrogen peroxide by dismutation. Hydroxyl radical is the most active oxygen free radical and is generated from hydrogen peroxide through the HaberWeiss reaction in the presence of ferrous iron. Hydroxyl radical alternatively may be formed through an interaction between superoxide radical and NO (Fubini and Hubbard, 2003). NO interacts with superoxide radical to form peroxynitrite that can further lead to the generation of peroxynitrous acid. Hydroxyl radical is produced from the spontaneous decomposition of
peroxynitrous acid. NO itself and peroxynitrite are also recognized as active oxygen free radicals. In addition to directly altering cellular function, NO may work through peroxynitrite that is potentially considered a more potent radical than NO itself (Pfeiffer et al., 2001). Oxidative stress in the brain occurs when the generation of ROS overrides the ability of the endogenous antioxidant system to remove excess ROS subsequently leading to cellular damage. Several cellular features of the brain suggest that it is highly sensitive to oxidative stress. For example, the brain is known to possess the highest oxygen metabolic rate of any organ in the body (Maiese, 2002). The brain consumes approximately twenty percent of the total amount of oxygen in the body. This enhanced metabolic rate leads to an increased probability that excessive levels of ROS will be produced. In addition, the brain tissues contain increased amounts of unsaturated fatty acids that can be metabolized by oxygen free radicals. Finally, the brain contains high levels of iron which have been associated with free radical injury (Herbert et al., 1994). Liposoluble iron chelators have been reported to lead to a reduction in ROS and protect neurons from permanent focal cerebral ischemia (Demougeot et al., 2004). Yet, given the increased risk factors for the generation of elevated levels of ROS in the brain, it is interesting to note that the brain also may suffer from an inadequate defense system against oxidative stress. Catalase activity in the brain is signicantly below other body organs. If one compares the catalase activity of the brain to the catalase activity in the liver, the brain has been shown to contain only 10% of the catalase activity present in the liver (Floyd and Carney, 1992). Oxidative stress represents a signicant pathway that leads to the destruction of both neuronal and vascular cells in the CNS. The production of ROS can lead to cell injury through cell membrane lipid destruction and cleavage of
210
DNA (Vincent and Maiese, 1999b; Wang et al., 2003). ROS result in the peroxidation of cellular membrane lipids (Siu and To, 2002), peroxidation of docosahexaenoic acid, a precursor of neuroprotective docosanoids (Mukherjee et al., 2004), the cleavage of DNA during the hydroxylation of guanine and methylation of cytosine (Lee et al., 2002), and the oxidation of proteins that yield protein carbonyl derivatives and nitrotyrosine (Adams et al., 2001). In addition to the detrimental effects to cellular integrity, ROS can inhibit complex enzymes in the electron transport chain of the mitochondria resulting in the blockade of mitochondrial respiration (Yamamoto et al., 2002). In cerebral vascular system, the cellular effects of ROS may lead to the destruction of endothelial cell (EC) membranes and an increase in endothelial cell permeability (Sakamaki, 2004).
2. Oxidative stress and neurodegenerative disease 2.1. Acute Oxidative brain damage is considered to be a signicant contributor to ischemic brain injury (Chong et al., 2004b). During cerebral ischemia, ROS, such as superoxide radicals, are released in signicant quantities and have been demonstrated at the interface of the cerebrovascular cell membrane (Yamato et al., 2003). Sources such as cyclooxygenase-2 (COX-2) and impaired mitochondrial function can lead to the release of ROS in the brain during cerebral ischemia and reperfusion (Bazan et al., 2002). Oxygen free radicals subsequently lead to reperfusioninduced injury following cerebral ischemia and are associated with delayed ischemic neuronal damage (Kitagawa et al., 1990). Several mechanisms may account for the cellular injury that results during exposure of ROS. Both ischemia and the subsequent failure of energy metabolism in the brain lead to the calcium-dependent activation of phospholipase A2. Phospholipase A2 can then cleave membrane phospholipids and release arachidonic acid (Mrsic-Pelcic et al., 2002). Superoxide radical is then produced with the metabolism of arachidonic acid by cyclooxygenase and lipooxygenase that are activated during reperfusion. Mitochondrial injury and the electron transport impairment also contribute to the production of superoxide radicals during focal cerebral ischemia and exacerbate brain infarction. ROS can precipitate endoplasmic reticulum damage during global brain ischemia that can be attenuated by copper zinc SOD overexpression (Hayashi et al., 2003). Cerebral ischemia also leads to NO production in the brain (Zhu et al., 2002). Superoxide readily reacts with NO leading to the formation of peroxynitrite that has been considered as a main product of NO contributing to reperfusion-induced brain damage following cerebral ischemia (Eliasson et al., 1999). Alternatively, NO may involve other signal transduction pathways such as protein kinase A and protein kinas C (Maiese and Boccone, 1995;
Maiese et al., 1993). Following cerebral ischemia, reperfusion leads to the signicant formation of superoxide, NO, and peroxynitrite on microvessels and surrounding end-feet. These ROS are believed to disrupt microvascular integrity resulting in cerebral hemorrhage and edema (GursoyOzdemir et al., 2004). In addition to the evidence for the production of ROS during the acute onset of cerebral ischemia and subsequent reperfusion injury, the ability to protect both neuronal and vascular tissue during cerebral ischemia with antioxidants or scavengers of ROS offers further support for the involvement of ROS during acute cerebral ischemia. For example, biologically active SOD fusion proteins can prevent hippocampal neuronal injury during transient forebrain ischemia (Sik Eum et al., 2004). Furthermore, novel free radical scavengers, such as 8-(4-uorophenyl)-2-((2E)-3phenyl-2-propenoyl)-1,2,3,4-tetra-hydropyrazolo[5,1c][1,2,4]triazine (FR210575), can signicantly reduce cortical damage by almost 40% in a transient model of cerebral ischemia and protect against apoptotic injury during permanent cerebral injury (Iwashita et al., 2003). Oxidative stress also has been suggested to play a crucial role in the pathology of TBI. Following TBI, increased ascorbyl free radical signals and reduced ascorbic acid has been demonstrated in rats (Awasthi et al., 1997). Additional investigations have shown an increase in lipid peroxidation, production of peroxynitrite, and impairment of the endogenous antioxidant system following TBI (Hall et al., 2004; Tyurin et al., 2000). Similarly, a sustained decrease in the total antioxidant reserve including ascorbate and glutathione has been observed in the cerebrospinal uid in infants and children after severe TBI (Bayir et al., 2002). The level of free radical induced products of lipid peroxidation and protein oxidation in the cerebrospinal uid also were increased following TBI (Bayir et al., 2002). In contrast, scavenging of ROS after TBI can improve neurological function and reduce cerebral injury (Marklund et al., 2001). 2.2. Chronic Oxidative stress is considered to play a signicant role in the onset and progression of AD (Maiese and Chong, 2004; Mattson, 2004). AD leads to a progressive deterioration of cognitive function with memory loss and is characterized by two pathologic hallmarks that consist of extracellular plaques of amyloid-b peptide aggregates and intracellular neurobrillary tangles composed of hyperphosphorylated microtubular protein tau. The b-amyloid deposition that constitutes the plaques is composed of a 3942 amino acid peptide (Ab), which is the proteolytic product of the amyloid precursor protein (APP) (Maiese and Chong, 2004). The association of oxidative stress with AD is dependent on several lines of evidence. The oxidative products of lipids, protein, and DNA have been reported in patients with AD. In the neocortex of the brain of individuals with AD, the
211
end product of lipid peroxidation, malondialdehyde (MDA), has been observed to be in signicantly higher quantities than in aged matched controls (Palmer and Burns, 1994). Elevated levels of another product of lipid peroxidation, 4-hydroxynonenal (4-HNE), also has been shown to be increased in the plasma of patients with AD (McGrath et al., 2001). 4-HNE is an aldehyde product of lipid peroxidation that can lead to caspase activation and apoptosis (Liu et al., 2000). In addition, HNE can become conjugated to the neuronal glucose transporters (Mark et al., 1997) and as a result has been suggested to be linked to impaired cellular glucose transport activity in AD (Masliah et al., 1996). Loss of specic plasma proteins, such as apolipoprotein E (apoE), also may play a pivotal role during oxidative stress induced injury during AD. In studies that examined cortical synaptosomes or neurons from transgenic mice lacking apoE, samples from apoE knockout mice possessed increased levels of oxidative stress and caspase activity during Ab exposure (Keller et al., 2000) as well as enhanced NO synthase activity (Law et al., 2003), suggesting a protective role for apoE. Although some investigators argue that observed lipid peroxidation in the brain of AD patients does not appear to correlate with the extent of neuritic plaques, neurobrillary tangles, or apoE genotype, lipid peroxidation does appear to directly coincide with progressive neuronal degeneration in AD patients (Montine et al., 1999). Other observations further support a role for ROS during AD. Selective oxidative modication of intracellular proteins, such as increased protein carbonyl levels in creatine kinase BB and b-actin, can be seen in AD (Chong et al., 2005b). Other evidence exists that suggests cellular injury during AD may result from both ROS as well as from impaired cellular repair mechanisms following oxidative injury. In one study, 8-hydroxy-20 -deoxyguanosine (8-OHdG), a marker of oxidative damage in intact DNA and as a free repair product during DNA repair mechanisms, was examined in the cerebrospinal uid of AD patients. Signicant elevations of 8-OHdG linked to intact DNA were observed in the cerebrospinal uid of AD patients, suggesting that these patients suffer from impaired DNA mechanisms. Yet, levels of free 8-OHdG, which are generated during normal cellular repair mechanisms, were found to be signicantly depleted in the cerebrospinal uid of AD patients, further supporting the premise of decient DNA repair mechanisms in these patients (Lovell et al., 1999). The neurotoxicity of Ab, a major component of AD pathogenesis, also is associated with cellular injury following ROS exposure. In mice overexpressing APP, the Ab deposits that are characteristically found in AD colocalize with several oxidative stress markers (Smith et al., 1998), suggesting that there exists a close correlation between oxidative stress and Ab deposition. In addition, agents that modulate ROS have been shown to reduce cellular injury during Ab exposure. Application of the free
radical antioxidant Vitamin E has been demonstrated to prevent neurotoxicity from Ab (Subramaniam et al., 1998). Over the last decade, a body of work has been generated to support the premise that Ab can directly lead to the generation of ROS. Early studies have demonstrated that Ab can lead to the generation of hydrogen peroxide and cell death in primary neuronal cultures (Behl et al., 1994). The ability of Ab to generate ROS may be a result of its methionine composition, since the substitution of methionine by valine, or the removal of the methionine in Ab, blocks ROS production, protein oxidation, and toxicity to primary hippocampal neurons (Varadarajan et al., 1999). Furthermore, free radical generation by Ab appears to be strongly inuenced by the aggregational state of the peptides, such that inhibition of Ab aggregation can reduce neuronal toxicity and free radical generation (Monji et al., 2001; Tomiyama et al., 1996). The generation of hydrogen peroxide by Ab may be mediated through mechanisms that are related to metal ion reduction (Huang et al., 1999) and the cellular ions of copper, zinc, and iron (Liu et al., 1999b) that are signicantly elevated in the senile plaques of patients with AD and can accelerate aggregation of Ab (Deibel et al., 1996). Channel formation during oxidative stress also may be a signicant factor in the pathogenesis of AD and Ab toxicity. Ab is able to spontaneously insert into planar lipid membranes to form selective, voltage-dependent, ionpermeable channels (Arispe et al., 1993; Mirzabekov et al., 1994). The subsequent channels formed may be calcium-permeable and lead to cellular toxicity through impaired calcium homeostasis (Lin et al., 1999; Sanderson et al., 1997) as well as through calpain activation (Boland and Campbell, 2003). Aggregates of Ab can further interact with the lipid bilayer and reduce membrane uidity to potentially impair cell function and promote cell injury (Kremer et al., 2001). Association with membrane phospholipids by Ab can be extensive in nature to disrupt both endosomal and plasma membranes through a pH dependent mechanism (McLaurin and Chakrabartty, 1996). Cellular injury as a result of ROS appears to proceed through apoptotic or programmed cell death (PCD) mechanisms. Accumulating evidence has been obtained from human and in vitro models of AD suggesting that apoptosis contributes to the neuronal loss during the disease. Data from in situ TUNEL (terminal deoxynucleotidyl transferase nick-end labeling) assays of brain tissues from individuals with AD demonstrate neuronal demise consistent with PCD. A correlation between the incidence of TUNEL-positive cells and plaque density also exists (Colurso et al., 2003). Levels of the apoptotic marker prostate apoptosis response-4 (Par-4) has been shown to be signicantly increased in the brains of patients with AD (Guo et al., 1998). Other lines of evidence link apoptotic cellular injury with APP and its proteolytic product Ab. In in vitro studies, expression of familial AD mutants of APP results in apoptotic neuronal injury (McPhie et al., 2003). It
212
is the cytoplasmic domain of APP that can lead to sustained apoptosis through c-Jun N-terminal kinase pathways (Hashimoto et al., 2003b). Additional studies have illustrated that direct application of Ab to neuronal cells can lead to chromatin condensation characteristic of apoptosis in cultured neurons. PD is a movement disorder characterized by resting tremor, rigidity, and bradykinesia. The pathophysiological basis of the symptoms rests upon the degeneration of dopaminergic neurons in the substantia nigra (SN). In some scenarios, it has been hypothesized that dopamine may even be a culprit in precipitating disease progression (Maiese et al., 2003). Dopamine may increase the rate of the generation of ROS species and subsequent oxidative products as well as decrease the reserve capacity of the brain to inactivate ROS (Zigmond et al., 2002). Other observations also support the premise that PD is a result of ROS generation. Cerebral iron, which can be a catalyst for the formation of hydroxyl radicals has been demonstrated to be increased in the basal ganglia of individuals with PD (Grifths et al., 1999). Elevations in oxidative products, such as lipid peroxides (Groc et al., 2001), protein carbonyls (Alam et al., 1997), and products of nucleic acid 8hydroxyguanosine (Zhang et al., 1999), have been observed in the SN of PD patients. Furthermore, when protein expression was compared in the SN from patients with PD and from controls, a total of 44 proteins expressed in the SN were identied by peptide mass ngerprinting with several representing mitochondrial and ROS scavenging proteins supporting oxidative stress involvement (Basso et al., 2004). As a correlation to the increased levels of these products in the brain, a systemic increase of the oxidized products of DNA, RNA, 8-hydroxyguanosine, and 8-hydroxy-20 -deoxyguanosine has been found in the serum and cerebrospinal uid of individuals with PD (Kikuchi et al., 2002). Given these studies, new approaches to treat patients with PD advocate the use of neuroprotective monoamine oxidase inhibitors combined with iron chelation therapy (Youdim et al., 2004). Huntingtons disease (HD) is an autosomal dominant neurodegenerative disease characterized by impairment of involuntary movement and cognitive impairment. Selective loss of neurons in the basal ganglia and cerebral cortex is one of the anatomical hallmarks of this disease. In patients with HD, the basal ganglia has increased levels of OHdG, suggestive of oxidative DNA damage (Browne et al., 1997). Furthermore, transgenic models of HD with R6/2 mice reveal increased OHdG in urine, plasma, and striatal microdialysates (Bogdanov et al., 2001). In other studies with transgenic R6/1 mice, dichlorouorescein (DCF), an index of ROS formation, was signicantly increased in R6/1 mice at 11, 19, and 35 weeks of age while the antioxidant catalase enzyme was signicantly depressed, suggesting an active role for ROS during the onset and progression of HD (Perez-Severiano et al., 2004). Amyotrophic lateral sclerosis (ALS), a disabling and fatal neurodegenerative disease, is characterized by the
progressive loss of muscle power as a result of the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Although approximately 10% of the reported cases are associated with inheritance, approximately 23% of observed ALS cases can be related to a mutation in the antioxidant enzyme copper zinc SOD (Rosen et al., 1993). ROS has been found to be increased in ALS in mice (Bogdanov et al., 1998). Additionally, the presence of oxidative products of protein, DNA, and lipid in the brains of ALS patients supports an involvement of ROS in the pathology of ALS (Liu et al., 1999a). Reduction in ROS may offer hope in providing some form of therapy for ALS. For example, mice expressing human mutant SOD1 G93A with EUK-8 and EUK-134, two synthetic SOD/catalase mimetics, have been shown to reduce oxidative stress and potentially prolong survival in animal models of ALS (Jung et al., 2001).
3. Early and late apoptotic programs Apoptosis, or PCD, is considered to be important for tissue re-modeling during development. Yet, this active process is recognized as a central pathway that can lead to a cells demise in a variety of tissues and has recently been identied in organisms as diverse as plants (Hatsugai et al., 2004). PCD consists of two independent processes that involve membrane phosphatidylserine (PS) exposure and DNA fragmentation (Maiese et al., 2004). Apoptotic injury is believed to contribute signicantly to a variety of disease states that especially involve the nervous system such as ischemic stroke, AD, PD, and spinal cord injury (Chong and Maiese, 2004; Li et al., 2004b). Outside of the nervous system, such as during cardiovascular injury, PCD also may be a signicant precipitant of cell death. Ischemicreperfusion injury can lead to apoptosis in cardiomyocytes (Cai et al., 2003). As an early event in the dynamics of cellular apoptosis, the biological role of membrane PS externalization can vary in different cell populations. In some cell systems, PS may be required for embryogenesis (Bose et al., 2004). Yet, in mature tissues, membrane PS externalization can become a signal for the phagocytosis of cells (Hong et al., 2004). In the nervous system, cells expressing externalized PS may be removed by microglia (Chong et al., 2003c; Li et al., 2004b). An additional role for membrane PS externalization in the vascular cell system is the activation of coagulation cascades. The externalization of membrane PS residues in ECs can promote the formation of a procoagulant surface (Chong et al., 2004a). In contrast to the early externalization of membrane PS residues, the cleavage of genomic DNA into fragments is considered to be a delayed event that occurs late during apoptosis (Dombroski et al., 2000; Jessel et al., 2002; Kang et al., 2003b; Maiese and Vincent, 2000). Several enzymes responsible for DNA degradation have been differentiated
213
based on their ionic sensitivities to zinc (Torriglia et al., 1997) and magnesium (Sun and Cohen, 1994). Calcium, a critical independent component that can determine cell survival (Weber, 2004), also may determine endonuclease activity through calcium/magnesium-dependent endonucleases such as DNase I (Madaio et al., 1996). Other enzymes that may disassemble DNA include the acidic, cation independent endonuclease (DNase II) (Torriglia et al., 1995), cyclophilins (Montague et al., 1997), and the 97 kDa magnesium-dependent endonuclease (Pandey et al., 1997). In the nervous system, three separate endonuclease activities are present that include a constitutive acidic cationindependent endonuclease, a constitutive calcium/magnesium-dependent endonuclease, and an inducible magnesium-dependent endonuclease (Vincent and Maiese, 1999b). The physiologic characteristics of the magnesium-dependent endonuclease, such as a pH range of 7.48.0, a dependence on magnesium, and a molecular weight of 95 108 kDa, are consistent with a recently described constitutive 97 kDa endonuclease in non-neuronal tissues. Exposure to ROS can precipitate apoptosis in neurons and ECs through multiple cellular pathways. Oxidative stress, such as NO or hydrogen peroxide, results in nuclei condensation and DNA fragmentation (Chong et al., 2003b; Goldshmit et al., 2001; Pugazhenthi et al., 2003; Vincent and Maiese, 1999b). In neurons, NO exposure produces apoptotic death in hippocampal and dopaminergic neurons (Chong et al., 2003a; Sharma and Ebadi, 2003; Vincent and Maiese, 1999a; Witting et al., 2000). Injury during NO exposure also can become synergistic with hydrogen peroxide to render neurons more sensitive to oxidative injury (de la Monte et al., 2003; Wang et al., 2003). Hydrogen peroxide also results in neuronal injury through impaired mitochondrial function and increased levels of proapoptotic gene products, such as CD95/Fas (de la Monte et al., 2000; Pugazhenthi et al., 2003; Vaudry et al., 2002). Externalization of membrane PS residues also occurs in neurons during anoxia (Chong et al., 2002b), NO exposure (Chong et al., 2003f), or during the administration of agents that induce the production of ROS, such as 6-hydroxydopamine (Salinas et al., 2003).
4. Microglial activation and inammation Modulation of extrinsic cell homeostasis through microglial activation is as vital to cellular survival as the maintenance of cellular DNA integrity. Microglia are monocyte-derived immunocompetent cells that enter the CNS during embryonic development and function similar to peripheral macrophages for the phagocytic removal of apoptotic cells. Some studies identify the generation of annexin I and membrane PS exposure that appears to be necessary to connect an apoptotic cell with a phagocyte (Arur et al., 2003). Secreted factors by either apoptotic or phagocytic cells, such as milk fat globule-EGF-factor 8
(Hanayama et al., 2004), fractalkine (Hatori et al., 2002), and lipid lysophosphatidylcholine (Lauber et al., 2003), also have been shown to assist with the phagocytic removal of injured cells. Yet, the translocation of membrane PS residues from the inner cellular membrane to the outer surface appears to be essential for the removal of apoptotic cells (Fadok et al., 2001; Kang et al., 2003b; Maiese and Vincent, 2000). The phospholipids of the plasma membrane are normally in an asymmetric pattern with the outer leaet of the plasma membrane consisting primarily of cholinecontaining lipids, such as phosphatidylcholine and sphingomyelin, and the inner leaets consisting of aminophospholipids that include phosphatidylethanolamine and PS. The loss of membrane phospholipid asymmetry leads to the externalization of membrane PS residues and serves to identify cells for phagocytosis (Chong et al., 2003d; Hoffmann et al., 2001; Kang et al., 2003b; Maiese and Chong, 2003). Expression of the phosphatidylserine receptor (PSR) on microglia also functions with cellular membrane PS externalization to activate microglia. Cells, such as neurons or ECs, exposed to ROS can lead to the induction of both microglial activation and microglial PSR expression. Treatment with an anti-PSR neutralizing antibody in microglia prevents this microglial activation (Chong et al., 2003b; Kang et al., 2003a) and application of PS directly results in microglial activation that can be blocked by a PSR neutralizing antibody (Chong et al., 2003b; Kang et al., 2003b), suggesting that both PS exposure in target cells and PSR expression in microglia are necessary for microglial recognition of apoptotic cells in the nervous system. Recognition of cellular membrane PS by the PSspecic receptors on microglia may require cofactors, such as Gas6 (Nakano et al., 1997) or other agents, such as integrin and lectin (Witting et al., 2000). Although microglia may assist with the removal of injured cells and cellular debri, these cellular scavengers of the brain may sometimes aggravate tissue inammation. Studies with microglia stimulated by phorbol myristate acetate have demonstrated the release of superoxide radicals. Application of scavenger agents for ROS, such as SOD or deferoxamine mesylate, in the presence of activated microglia can prevent cellular injury. These studies suggest that oxidative stress generated by microglia can be responsible for cellular injury (Tanaka et al., 1994). Microglia may lead to cellular damage in disease entities, not only through the generation of ROS products (Sankarapandi et al., 1998) but also through the production of cytokines and the demise of neighboring neurons and ECs (Benzing et al., 1999; Mehlhorn et al., 2000). In HD and ALS, signicant microglial activation has been reported in regions of the nervous system that are specic for these disease entities (Obal et al., 2001; Singhrao et al., 1999). During ischemic injury to cells, activation of microglia can parallel the induction of cellular apoptosis and correlate well with the severity of the ischemic insult (Chong et al., 2004a;
214
Kang et al., 2003b). Microglia promote the production of pro-inammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin-1b, free radicals such as NO and superoxide (Sankarapandi et al., 1998), and fatty acid metabolites such as eicosanoids that can precipitate cell death (Liu and Hong, 2003). TNF-a production by microglia may be linked to neurodegeneration by increasing the sensitivity of neurons to free radical exposure (Combs et al., 2001). In several neurodegenerative diseases, microglial activation has been identied through glial cultures in autopsy specimens (Lue et al., 1996). For example, expression of markers that are indicative of microglial activation was found to be signicantly increased in patients with AD (Rogers and Lue, 2001). Application of a position emission tomography marker [11C](R)-PK11195 for microglial activation in patients with mild and early AD also has demonstrated microglial activation in regions of the entorhinal, parietal, and cingulate cortex, suggesting that microglial activation is an early event in the pathogenesis of the disease (Cagnin et al., 2001). One of the major pathogens of AD, namely Ab, has been shown to lead to inammatory cell injury through a variety of routes. Ab can not only precipitate a signicant inammatory response with microglial activation and the secretion of TNF-a (Bornemann et al., 2001), but also Ab can elicit the neuronal expression of inducible nitric oxide synthase, peroxynitrite production, and neuronal apoptosis during an acute inammatory response (Combs et al., 2001). Microglial cells also co-localize with the perivascular deposits of Ab and microglial activation correlates with the development of amyloid plaques (Sheng et al., 1997). Ultrastructural three-dimensional reconstruction of human amyloid plaques in different stages of development illustrates that the number of microglia parallels a progressive increase in brillar deposition and the size of brillar plaque (Wegiel et al., 2000). The generation of ROS by microglia during events such as Ab deposition suggests that microglia may play an important role during the development of neurodegenerative diseases.
5. Attempted cell cycle induction in post-mitotic cells The attempted reentrance into the cell cycle in post-mitotic neurons can trigger apoptosis (Becker and Bonni, 2004). In the CNS, post-mitotic neurons are incapable of differentiation, but they continue to possess the ability to enter into the cell cycle. During a cellular insult, deregulation of cell cycle proteins, such as cyclin, cyclin-dependent kinase (CDK), and the retinoblastoma protein, can ensue (Padmanabhan et al., 1999). The deciency of several essential components for the complete execution of the cell cycle in post-mitotic neurons is believed to be deleterious to neurons. Several studies have provided direct evidence that cell cycle induction in postmitotic neurons can activate cellular mechanisms that lead to
neuronal apoptosis (El-Khodor et al., 2003; Ino and Chiba, 2001; Konishi and Bonni, 2003; Lin et al., 2001; Rideout et al., 2003; Tetsu and McCormick, 1999). Investigations that examine ROS as a stimulus for cell cycle induction reveal that distinct components of apoptotic injury, membrane PS exposure and genomic DNA fragmentation, occur in concert with early and late phases of cell cycle induction (Lin et al., 2001). Oxidative injury associated with ROS may lead to attempted cell cycle induction in neurons. The induction of oxidative stress in sympathetic neurons by either dopamine, which produces free radicals during its metabolism, or by hydrogen peroxide leads to the increased expression of cell cycle related genes that include cyclin B and CDK5 prior to the induction of neuronal apoptosis (Shirvan et al., 1998). Furthermore, antioxidants that include N-acetyl-L-cysteine (LNAC) and N-acetyl-D-cysteine (DNAC) can prevent DNA fragmentation during trophic factor deprivation through mechanisms that may involve the inhibition of cell cycle progression in neuronal cell lines (Ferrari et al., 1995). Acute injury paradigms have suggested a potential role for ill-fated cell cycle induction in neurons. Cell cycle proteins (cyclin A, cyclin D, CDK2, CDK4) have been co-localized with apoptotic cells following middle cerebral artery occlusion (Li et al., 1997b). Although evidence for cell cycle induction during cerebral ischemia may be partially associated with neurogenesis (Taguchi et al., 2004), ischemic insults also can lead to aberrant cell cycle induction that may have ramications for both acute and long-term consequences on cellular function (Wen et al., 2004). Other neurodegenerative diseases, such as AD, also appear to rely upon attempted cell cycle induction, at least in part, to yield subsequent neuronal cell loss (Arendt et al., 2000; Busser et al., 1998; Maiese, 2001; Raina et al., 2000). In clinical specimens from AD patients, the cell cycle regulators P16 and CDK4 have increased expression in regions such as the hippocampus (McShea et al., 1997). In addition, expression of other components of the cell cycle, such as cyclin D, CDK4, proliferating cell nuclear antigen (PCNA), and cyclin B1 have been shown to be present in patients with AD in regions that include the hippocampus, subiculum, locus coeruleus, and dorsal raphe nuclei. A close association appears to exist between injured cells and cell cycle protein expression, since staining for cell cycle proteins have been shown to be absent in brain regions without neuronal injury of AD patients and in age-matched brains (Busser et al., 1998). Increased accumulation of cell cycle kinases, such as CDK5, also has been found in neurons that are developing neurobrillary tangles (Pei et al., 1998). Interestingly, in patients with mild cognitive impairment, many of which can progress to develop AD (Bennett et al., 2002), cell cycle proteins, such as cyclin D, cyclin B, and PCNA, are signicantly increased in the hippocampus and basal nucleus (Yang et al., 2003). Experimental models of AD have provided further evidence that cell cycle induction in post-mitotic neurons
215
can activate cellular mechanisms that lead to neuronal apoptosis. For example, application of Ab (140), Ab (1 42), and its active fragment Ab (2535) in neurons can result in the induction of cyclin D1, cyclins E and A, and the phosphorylation of the retinoblastoma protein. The activation of the upstream cyclin-dependent kinases (CDK)4/5/6 appears to be required for the induction of apoptosis in neurons by Ab, since inhibition of CDKs can prevent Ab induced neuronal apoptosis (Alvarez et al., 2001; Giovanni et al., 1999). Cell cycle proteins can contribute to neurobrillary tangle development. Expression of familial AD mutants of the APP in primary neurons can precipitate apoptotic injury through cell cycle induction and p21 mediated pathways (McPhie et al., 2003). CDK5 also has been identied as a critical regulator of the tau protein which leads to neurobrillary tangles. CDK5 can phosphorylate tau directly (Flaherty et al., 2000). Furthermore, phosphorylation of tau by Ab can be blocked by treatment with antisense against p35, a protein that is cleaved to the truncated form p25 which can activate CDK5. This work provides evidence that Ab requires both the cleavage of p35 and the activation of CDK5 to lead to tau phosphorylation (Town et al., 2002). Correlative work has shown that p25 also accumulates in neurons of patients with AD (Patrick et al., 1999). In addition, overexpression of the p25/Cdk5 complex in cultured primary neurons leads to cytoskeletal disruption, the hyperphosphorylation of tau, and apoptosis (Patrick et al., 1999), suggesting that induction of cell cycle proteins can be a signicant precipitant for neuronal degeneration.
6. Induction of the Wnt pathway Wnt proteins, named after the Drosophilia protein wingless and the mouse protein Int-1, represent a large family of secreted cysteine-rich glycosylated proteins. This novel family of proteins are intimately involved in cellular signaling pathways that play a role in a variety of processes that involve embryonic cell patterning, proliferation, differentiation, orientation, adhesion, survival, and apoptosis (Chong and Maiese, 2004; Nelson and Nusse, 2004; Patapoutian and Reichardt, 2000). Nineteen of the 24 Wnt genes that express Wnt proteins have been identied in the human. In addition, greater than 80 target genes of Wnt signaling pathways have been demonstrated in human, mouse, Drosophilia, Xenopus, and Zebrash. This representation encompasses several cellular populations, such as neurons, cardiomyocytes, endothelial cells, cancer cells, and pre-adipocytes (Nusse, 1999). Wnt binds to Frizzled transmembrane receptors on the cell surface to activate downstream signaling events (Fig. 1). These involve at least two intracellular signaling pathways that are considered of particular importance. One pathway controls target gene transcription through b-catenin, generally referred to as the canonical pathway that involves
Fig. 1. Modulation of apoptotic injury by Wnt and Akt pathways. The Wnt canonical signaling pathway is initiated by activation of its transmembrane receptor Frizzled (Friz) and the co-receptor lipoprotein related proteins 5 and 6 (LRP-5/6), resulting in the recruitment and activation of disheveled which inhibits glycogen synthase kinase (GSK)-3b. When active, GSK-3b functions with adenomatous polyposis coli (APC) and the phosphorylation of Axin to result in b-catenin phosphorylation and its subsequent degradation. In contrast, free b-catenin translocates to the nucleus and activates lymphocyte enhancer factor (Lef) and T cell factor (Tcf) to stimulate Wntresponsive genes. The serinethreonine kinase Akt functions as a downstream target of phosphoinositide 3 kinase (PI 3-K). PI 3-K phosphorylates glycerophospholipid phosphatidylinositol 4,5-bisphosphate, yielding phosphatidylinositol 3,4-bisphosphate (PIP2) and phosphatidylinositol 3,4,5trisphosphate (PIP3). As a cytosolic protein, Akt translocates to the cell membrane following its binding to PIP2 and PIP3 and becomes activated through phosphorylation by phosphoinositide-dependent kinase 1 (PDK1). Wnt also may activate Akt through the Wnt-1 induced secreted protein (WISP-1). Akt targets GSK-3b through phosphorylation, resulting in the inactivation of GSK-3b and blocking the degradation of b-catenin. Furthermore, phosphorylation of the translation initiation factor 2B (eIF2B) is prevented to prevent the release of cytochrome c (Cyto c). In addition, Akt inactivates FOXO3a and Bad to inhibit induction of Bim and restore Bcl-xL function.
Wnt1, Wnt3a, and Wnt8 and functions through b-catenindependent pathways. Another pathway pertains to intracellular calcium (Ca2+) release which is termed the noncanonical or Wnt/Ca2+ pathway consisting primarily of Wnt4, Wnt5a, and Wnt11 that functions through non-bcatenin-dependent pathways, such as the planar cell polarity (PCP) pathway and the Wnt-Ca2+-dependent pathways (Kuhl et al., 2000; Nusse, 1999; Patapoutian and Reichardt, 2000). As one of the best characterized members of the Wnt family, Wnt1 was rst identied as a proto-oncogene in mammary carcinomas, but recently has been illustrated to play a critical role in neuronal development (Tang et al., 2002). Wnt functions by binding to the transmembrane receptor Frizzled and the co-receptor lipoprotein related proteins 5 and 6 (LRP-5/6) (Wehrli et al., 2000) followed by recruitment of disheveled, the cytoplasmic bridging molecule, to inhibit glycogen synthase kinase (GSK-3b) (Ikeda et al., 1998; Papkoff and Aikawa, 1998). The inhibition of GSK-3b prevents phosphorylation of b-catenin and its
216
degradation. The free b-catenin translocates to the nucleus where it activates lymphocyte enhancer factor (Lef) and T cell factor (Tcf) (Ishitani et al., 2003) leading to stimulation of Wnt-response genes (Fig. 1). In some cell systems, Wnt1 signaling has been associated with the control of apoptosis. Wnt-1 prevents apoptosis through b-catenin/Tcf transcription mediated pathways (Chen et al., 2001; Rhee et al., 2002). Overexpression of exogenous Wnt1 results in the protection of cells against c-myc induced apoptosis through induction of b-catenin, cyclooxygenase-2, and Wnt1 induced secreted protein (WISP-1) (You et al., 2002). Wnt1 signaling also can inhibit apoptosis through prevention of cytochrome c release from mitochondria and the subsequent inhibition of caspase 9 activation (Chen et al., 2001). The adenomatous polyposis coli (APC) gene, a member of the Wnt pathway, appears to represent another mechanism that regulates PCD. The APC gene functions to cleave b-catenin leading to the downregulation of transactivation of Tcf/Lef (Tetsu and McCormick, 1999). Without Tcf/Lef activity, APC is then permitted to increase the activities of caspase 3, caspase 7, and caspase 9 and lead to the cleavage of poly(ADPribose) polymerase (PARP) to enhance the vulnerability of cells to apoptosis (Chen et al., 2003). In the nervous system, the non-canonical Wnt pathway has been shown to be expressed in the hippocampus of mice and can increase dendritic branching in cultured neurons (Rosso et al., 2005). Wnt signaling through Wnt1 also is able to guide early neural crest stem cells to develop into sensory neural cells rather than maturing into other potential neural crest cell derivatives (Lee et al., 2004). Yet, in regards to cytoprotection in the brain that involves the Wnt pathway, limited studies are available. The work that is presently available suggests that enhanced Wnt activity may function through several cellular pathways to prevent apoptosis during neuronal or vascular injury. Conditioned media with Wnt3a activity or the application of a GSK-3b inhibitor can block hydrogen peroxide induced mitochondrial dysfunction and apoptotic DNA fragmentation (Shin et al., 2004). Other work illustrates that Wnt signaling may foster specic protection against cellular destruction and inammatory injury by maintaining genomic DNA integrity and cellular membrane PS asymmetry (Chong et al., 2004b; Maiese and Vincent, 2000). Wnt1 overexpression in primary hippocampal neurons protects cells against oxidative stress or Ab toxicity that increases cell survival and prevents PS exposure and DNA degradation (Chong et al., 2004b). In addition, agents that combine non-steroidal anti-inammatory compounds with a cholinesterase inhibitor are believed to prevent neurotoxicity against Ab. The mechanism of protection has been suggested to involve the enhancement of non-amyloidogenic APP cleavage that leads to a decreased production of endogenous Ab through the Wnt pathway (Farias et al., 2005). Loss of Wnt activity may lead to cellular injury or dysfunction in the CNS during oxidative stress. Wnt1
expression has been demonstrated in the brains of individuals affected by neuropsychiatric disorders (Miyaoka et al., 1999). Furthermore, retinal degeneration during retinitis pigmentosa with the progressive loss of photoreceptors has been associated with increased secretion of Frizzled-related protein-2, a Wnt inhibitory protein, suggesting that loss of Wnt signaling may contribute to retinal neurodegeneration (Jones et al., 2000). Additional work demonstrates that a mutation in the membrane-type Frizzled-related protein gene may be involved in retinal photoreceptor degeneration (Kameya et al., 2002). During AD, neurotoxicity of Ab in hippocampal neurons has been linked to increased levels of GSK-3b and loss of bcatenin. Decreased production of Ab can occur during the enhancement of protein kinase C (PKC) activity (Savage et al., 1998) which may be controlled by the Wnt pathway (Garrido et al., 2002). The proteolytic processing of APP during AD also has been closely linked to the Wnt pathway through presenilin 1 (PS1) and disheveled. PS1 is required for the processing of APP and has been shown to downregulate Wnt signaling and interact with b-catenin to promote its turnover (Soriano et al., 2001). Disheveled, a known downstream transducer of Wnt signaling pathway, also can regulate the a-secretase cleavage of APP through PKC/mitogen-activated protein kinase dependent pathways, increasing soluble production of APP (sAPP) (Mudher et al., 2001). Overexpression of mouse disheveled-1 and -2 inhibits GSK-3b mediated phosphorylation of tau protein and may thus prevent formation of neurobrillary tangles during AD (Wagner et al., 1997). Thus, disheveled may increase neuronal protection during neurodegenerative disorders through sAPP production and reduction in tau phosphorylation.
7. Akt as an essential regulatory element 7.1. Activation and expression of Akt Protein kinase B (PKB) is ubiquitously expressed in mammals but is initially present at low levels in the adult brain (Owada et al., 1997). Three family members of this serine/threonine kinase are now known to exist that were termed Akt after the molecular cloning of the oncogene v-Akt and two human homologs (Staal, 1987; Staal et al., 1988). They are PKBa or Akt1, PKBb or Akt2, and PKBg or Akt3 (Chong et al., 2005a). Akt is part of the AGC (cAMPdependent kinase/protein kinase G/protein kinase C) superfamily of protein kinases and consists of three functional domains. The N-terminal pleckstrin homology (PH) domain provides binding sites for membrane phospholipids, which are involved in the recruitment of Akt to the plasma membrane (Frech et al., 1997). The catalytic domain of Akt has specicity for serine or threonine residues of proteins that are substrates for Akt. It is interesting to note that the three isoforms of Akt share the same regulatory phosphor-
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Table 2 Substrates of Akt that determine apoptotic cell injury Substrate FOXO3a GSK-3b Function Activation leads to apoptotic injury, cell cycle progression; contributes to oxidative stress; possesses caspase 3 cleavage sequence Phosphorylates b-catenin, eIF2B, CREB, and tau protein to result in apoptosis and the formation of neurobrillary tangles; promotes cytochrome c release, caspase activation Oxidative stress activates Bad;, phosphorylation of Bad by Akt blocks apoptotic injury, prevents cytochrome c release Leads to the induction of multiple anti-apoptotic genes; blocks caspase activity; protects through activation of Bcl-xL Selected references Brunet et al. (1999); Medema et al. (2000); Kops et al. (2002) and Chong et al. (2004c)
217
Somervaille et al. (2001); Kirschenbaum et al. (2001); Pap and Cooper (2002) and Koh et al. (2003) Datta et al. (1997); Simakajornboon et al. (2001); Chong et al. (2003b) and Uchiyama et al. (2004) Wang et al. (1998); Chen et al., (2000); De Smaele et al. (2001) and Tang et al. (2001)
Bad NF-kB
Note: CREB, cAMP-response element-binding protein; eIF2B, the translation initiation factor 2B; GSK-3b, glycogen synthase kinase-b; IKK, IkB kinase; JNK, c-Jun-amino terminal kinase; NF-kB, nuclear factor-kB.
ylation sites but that splice variants of Akt that lack the C-terminal hydrophobic motif (HM) possess lower specic activity than full-length isoforms, suggesting that the C-terminal HM is vital to stimulate Akt activity (Brodbeck et al., 2001; Yang et al., 2002) (Table 2). Activation of Akt is dependent upon PI 3-K (Fig. 1). The activation of the receptor tyrosine kinase (RTK) and the G protein-coupled receptor (CPCR) are required to activate PI 3-K. Trophic factors or cytokines can stimulate the recruitment of PI 3-K to the plasma membrane. Following activation, PI 3-K phosphorylates membrane glycerophospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] resulting in the production of phosphatidylinositol 3,4,5trisphosphate (PIP3) and phosphatidylinositol 3,4-bisphosphate (PIP2). Both PIP2 and PIP3 bind with equal afnity to Akt and are required for Akt activation (Thomas et al., 2002). The critical step for activation of Akt is its transition from the cytosol to the plasma membrane, which is accomplished by the binding of Akt to PIP2 and PIP3 through its PH domain (Stephens et al., 1998). As a result of this sequence of events, Akt becomes available for phosphorylation by several upstream kinases. The phosphorylation of two major residues, Thr308 and Ser473, are considered necessary for the activation of Akt. The site of Thr308 is located within the activation T-loop of Akt1. For Akt2 and Akt3, the equivalent residues are Thr309 and Thr305, respectively (Walker et al., 1998). These phosphorylation sites are believed to be critical for the activation of Akt. Yet, the phosphorylation of Ser473 at the C-terminal HM domain also is necessary for the complete activation of Akt (Bellacosa et al., 1998). The phosphorylation of Thr308 is dependent upon its upstream kinase, 3phosphoinositide-dependent kinase-1 (PDK1) (Wick et al., 2000). PDK1 cannot directly phosphorylate Ser473, but a distinct phosphoinositide-dependent kinase PDK2 (Ser473 kinase) has been postulated to promote Akt phosphorylation on Ser473. The existence of PDK2 is pending further conrmation. A number of pathways can control the biological activity of Akt. Some lipid phosphatases have been shown to negatively modulate the activity of Akt. The phosphatase
and tensin homolog deleted from chromosome 10 (PTEN) appears to be a critical regulator of PI 3-K signaling. PTEN can dephosphorylate tyrosine-, serine-, and threoninephosphorylated peptides (Lee et al., 1999). PTEN negatively regulates PI 3-K pathways by specically dephosphorylating PIP2 and PIP3 at the D3 position (Maehama and Dixon, 1998). As a result, a reduction in the membrane phospholipid pool that is necessary for the recruitment of Akt can ensue during PTEN activity. Other lipid phosphatases, such as SHIP (SH2 domaincontaining inositol phosphatase), can regulate Akt activity. SHIP is an inositol 50 -phosphatase that dephosphorylates inositides and phosphoinositides on the 50 -position resulting in the transformation of PIP3 into PIP2. The SHIP2 gene appears to modulate insulin signaling, since targeted disruption of this gene leads to increased insulin sensitivity that occurs as a result of enhanced phosphorylation of Akt2 at the plasma membrane (Sasaoka et al., 2004). In other cell systems that involve hematopoietic proliferation, SHIP also functions to block activation of Akt (Carver et al., 2000). The Src homology domain 2 (SH2)-containing tyrosine phosphatases (SHP) also have been implicated in the control of the Akt pathway. In regards to SHP1 and SHP2, SHP1 is predominantly expressed in hematopoietic cells, but SHP2 is more ubiquitously expressed and occurs in the nervous system (Chong et al., 2003f). Through the activation of Akt, SHP1 can selectively bind and dephosphorylate PTEN to reduce the stability of this protein (Lu et al., 2003). SHP2 also appears to modulate the activation of Akt (Ivins Zito et al., 2004) to prevent cellular death from apoptosis through inhibition of either caspase 1- or 3-like activities (Chong et al., 2003f; Ivins Zito et al., 2004). Alternate cellular systems are responsible for the enhancement of Akt activity. Carboxyl-terminal modulator protein (CTMP) also can negatively regulate the activity of Akt. CTMP is a 27 kDa protein that binds specically to the carboxyl-terminal regulatory domain of Akt1 at the plasma membrane (Maira et al., 2001). The binding of CTMP to Akt1 decreases the activity of Akt1 by inhibiting the phosphorylation of Akt1 on Ser473 and Thr308 (Maira et al., 2001). The T cell leukemia/lymphoma 1 (TCL1) protein
218
functions as a co-activator of Akt. TCL1 can stabilize mitochondrial membrane potential and promote cell proliferation and survival (Laine et al., 2000). TCL1 binds to Akt1 and increases Akt1 kinase activity to promote its nuclear translocation (Pekarsky et al., 2000). Additional work has shown that TCL1 binds to the PH domain of Akt and the formation of TCL1 trimers facilitate the formation of the Akt/TCL1 complex. Within this complex, Akt is phosphorylated and activated in vivo (Laine et al., 2000). Akt activity also can be facilitated by a 90 kDa heat shock protein (Hsp90). Hsps are characterized by their mass in kilodaltons, are induced in response to heat in essentially all organisms, and are highly conserved between different species. Hsps, such as Hsp90, can be cytoprotective, such as preventing cell injury against heat thermal stress (Beere et al., 2000; Kalwy et al., 2003; Latchman, 2004). Akt binds to Hsp90 through its 229309 residues resulting in stabilization of the phosphorylated Akt. Inhibition of Akt binding to Hsp90 leads to dephosphorylation of Akt by protein phosphatase 2A (PP2A) and induction of apoptosis (Sato et al., 2000). Intracellular Akt also can become complexed with Hsp90 and Cdc37. As a result of this association, increased Akt activity is present but is closely dependent upon the presence of Hsp90 in the complex (Basso et al., 2002). The cellular expression of Akt can vary in a variety of tissues and cells. Akt1 is the most highly expressed isoform. Although Akt2 is expressed at a lower level than Akt1, signicant expression of Akt2 occurs in insulin-responsive tissues, such as skeletal muscle, liver, heart, kidney, and adipose tissue (Altomare et al., 1995). In the CNS, the expression of Akt1 and Akt2 can be observed at increased levels during development but is gradually decreased during postnatal development (Owada et al., 1997). Yet, in the adult brain, expression of Akt1 and Akt2 is initially weak with a dramatic increase in the expression of Akt1 mRNA and Akt1 protein in cells that are subjected to injury (Chong et al., 2004a; Kang et al., 2003b; Owada et al., 1997), suggesting that Akt may play an important role during cell injury. In contrast to Akt1 and Akt2, Akt3 is expressed only in a limited number of tissues, such as in the brain and testes, with lower expression evident in skeletal muscle, pancreas, heart, and kidney (Nakatani et al., 1999). 7.2. Akt as a modulator apoptotic injury and inammation during ROS exposure Akt is a critical survival factor that can modulate cellular pathways in both the central and peripheral nervous systems. Early studies have demonstrated that overexpression of Akt in CNS neurons prevents apoptosis during growth factor withdrawal (Datta et al., 1997). Similar investigations that employed superior cervical ganglion neurons also illustrated that Akt was necessary to prevent cell death during nerve growth factor withdraw (Philpott et al., 1997). Additional studies have shown that Akt can be both necessary and sufcient for the survival of neurons, since expression of a
dominant-negative Akt or inhibition of PI 3-K yields apoptotic cell death during trophic factor administration (Crowder and Freeman, 1998) and precipitates cell death during oxidative stress (Kang et al., 2003a,b). Akt also impacts upon the function and survival of cerebral vascular ECs. Recent investigations have shown that Akt modulates cerebral blood ow and vasomotor tone (Luo et al., 2000) and prevents apoptotic injury during compromises in mitochondrial function and caspase regulation (Chong et al., 2002b, 2004a). Further work has illustrated an important role for Akt for the survival of cells during a number of injury paradigms. Enhanced Akt activity can foster cell survival during free radical exposure (Chong et al., 2003b; Matsuzaki et al., 1999), matrix detachment (Rytomaa et al., 2000), neuronal axotomy (Namikawa et al., 2000), DNA damage (Chong et al., 2002b, 2004a; Henry et al., 2001; Kang et al., 2003a), anti-Fas antibody administration (Suhara et al., 2001), oxidative stress (Chong et al., 2003b; Kang et al., 2003a,b; Yamaguchi and Wang, 2001), hypoxic preconditioning (Wick et al., 2002), Ab exposure (Martin et al., 2001), and transforming growth factor-b (TGF-b) application (Conery et al., 2004). Akt possesses the ability to offer a broad level of cytoprotection in cells through both intrinsic cell mechanisms that involve the maintenance of genomic DNA and the exposure of membrane PS residues. Through the overexpression of a myristoylated (active) form of Akt and a kinase-decient dominant-negative Akt, recent work has shown that Akt is both necessary and sufcient to protect cells, such as neurons and ECs from injury associated with oxidative stress (Chong et al., 2003b; Kang et al., 2003a,b). Overexpression of myr-Akt signicantly protects cells from free radical injury and prevents degradation of genomic DNA (Fig. 2). Yet, cells with a dominant-negative overexpression that lack kinase activity suffer a signicant loss in cell survival during oxidative stress. Further studies have suggested that through the inhibition of PI 3-K phosphorylation of Akt or through the overexpression of a kinase-decient dominant-negative Akt, endogenous cellular reserves of Akt also can provide an additional level of protection during cell injury that can function in concert with the exogenous activation of Akt to achieve increased cellular protection (Chong et al., 2004a; Kang et al., 2003a,b). It is important to note that activation of Akt is not always desirable. Under some conditions, enhanced cellular survival during Akt activation in cells that are targeted for destruction, such as in neoplastic cells, could undermine treatment as well as foster the growth of a neoplasm. As a result, recent work has identied Akt as a potential target to block during the treatment of non-small cell lung cancers that contain mutations in the epidermal growth factor (Sordella et al., 2004). Akt prevents inammatory cell demise through extrinsic cellular mechanisms that involve membrane PS exposure and the subsequent activation of microglia. Enhanced Akt activity can prevent cellular membrane PS externalization in
219
Fig. 2. Overexpression of Akt1 prevents cellular injury and DNA degradation during oxidative stress. Representative images illustrate DNA fragmentation with TUNEL and cell survival with a trypan blue dye exclusion (TB) methods in both wild-type and myristolated (myr)-Akt1 (active Akt1) transfected cerebral microvascular endothelial cells (ECs) 24 h following exposure to a NO donor (NOC-9, 1000 mM). NO induced DNA fragmentation and TB staining was evident in wild-type cells (wild-type/NO), but is absent in cells overexpressing Akt1 (myr-Akt1/NO).
both neurons and ECs during a variety of insults that involve anoxia, free radical exposure, and oxygen-glucose deprivation (Chong et al., 2002b, 2004a; Maiese et al., 2004). In addition, Akt appears to employ the modulation of membrane PS externalization to prevent microglial activation (Kang et al., 2003b). Activation of Akt can prevent membrane PS exposure on injured cells and block the activation of microglia that are exposed to media taken from cells that overexpress active, phosphorylated Akt during cellular injury (Kang et al., 2003a,b). Cytoprotective agents, such as nicotinamide and erythropoietin (EPO), also employ mechanisms that involve Akt to regulate microglial activation and proliferation (Chong et al., 2003d; Li et al., 2004b; Maiese et al., 2004). These protective agents block membrane PS exposure on cells and possibly prevent the shedding of membrane PS residues that is known to occur during apoptosis (Simak et al., 2002). In addition to targeting the activity of membrane PS exposure and microglial activation, Akt also may directly address cellular inammation by inhibiting several pro-inammatory cytokines, such as TNF-a (Fontaine et al., 2002). In addition to its ability to protect cells against apoptotic and inammatory injury, Akt can function to either reduce or prevent cellular destruction from ROS. For example, ROS generated by hydrogen peroxide can lead to the endogenous activation of Akt in several cell lines such as Hela, A549, and MCF-7 cells (Wang et al., 2000). In human glioblastoma cell lines, hydrogen peroxide also leads to a marked phosphorylation of Akt (Sonoda et al., 1999). Generation of peroxynitrite by sodium nitrite and acidic hydrogen peroxide also results in a time and dose-dependent activation of Akt followed by inactivation of GSK-3b in human skin primary broblast cells (Klotz et al., 2000). Akt activation during ROS in several neuronal and vascular cell systems has been demonstrated in neuronal cell lines (Kang et al., 2003a,b; Salinas et al., 2003), primary hippocampal and cortical neurons (Chong et al., 2003b,e; Crossthwaite et al.,
2002; Matsuzaki et al., 1999) and cerebral vascular ECs (Chong et al., 2002b, 2004a). 7.3. Akt can provide the stimulus for altering the course of neurodegenerative disease As a result of the broad protective nature of Akt, it may come as no surprise to learn that many agents or growth factors appear to prevent apoptotic cellular injury through Akt activation. In the vascular system, angiopoietin-1 is an endothelium-specic ligand essential for embryonic vascular stabilization, branching, morphogenesis, and postnatal angiogenesis. Angiopoietin-1 also supports endothelial cell survival and prevents apoptosis through the activation of Akt that requires a PI 3-K dependent pathway (Papapetropoulos et al., 2000). Furthermore, in the cardiovascular system, myocardial protection by insulin during myocardial ischemia/reperfusion is abolished by PI 3-K inhibition, suggesting that cardioprotection of insulin is mediated by Akt activation (Jonassen et al., 2001; Li et al., 2004a; Maiese et al., 2005). The involvement of the PI 3-K/Akt pathway also has been demonstrated during the protection of retinal ganglion cells from axotomy (Kermer et al., 2000). A number of trophic factors and cytokines, such as EPO, may depend upon Akt to offer cellular protection (Maiese et al., 2003). EPO can phosphorylate Akt and is dependent upon the activation of PI 3-K and Janus kinase 2 (Jak2) (Chong et al., 2002b; Witthuhn et al., 1993). Activation of Jak2 promotes the phosphorylation of tyrosine residues in the intracellular portion of the EPO receptor (Witthuhn et al., 1993). Phosphorylation of the last tyrosine of the EPO receptor initiates binding of the 85 kDa regulatory subunit of PI 3-K, a heterodimer consisting of a 110 kDa catalytic subunit and an 85 kDa regulatory subunit. As a result of the binding of the 85 kDa regulatory subunit, the 110 kDa catalytic subunit becomes active and leads to the phosphorylation of Akt.
220
Central to the ability of EPO to prevent cellular apoptosis is the activation of Akt by EPO (Maiese et al., 2004). During anoxia or free radical exposure, expression of the active form of Akt (phospho-Akt) is increased (Kang et al., 2003a,b). EPO can signicantly enhance the activity of Akt during oxidative stress and prevent inammatory activation of microglia (Chong et al., 2003a,b,e). This up-regulation of Akt activity during injury paradigms appears to be vital for EPO protection, since prevention of Akt phosphorylation blocks cellular protection by EPO (Chong et al., 2003a,b,e). Through the regulation of the PI 3-K/Akt dependent pathway, EPO can prevent cellular apoptosis following Nmethyl-D-aspartate toxicity (Dzietko et al., 2004), hypoxia (Chong et al., 2002b), and oxidative stress (Chong et al., 2003a,b,e). Given the intimate association between Akt and cytoprotective agents, Akt may be viewed as an essential target for therapeutic strategies against a number of diseases that involve apoptotic cell death. The association of familial AD with mutations in APP suggests that wild-type APP may have a protective ability against toxic insults to cells, since mutations in APP impair its ability to offer resistance against oxidative stress. Recent work has suggested that protection by wild-type APP against ROS may require the PI 3-K/Akt pathway, since dominant-negative forms of Akt eliminated the protective capacity of wild-type APP (Kashour et al., 2003). Furthermore, overexpression of Akt1 can attenuate apoptosis during Ab exposure (Martin et al., 2001). In models of Parkinsons disease that employ the neurotoxin 1methyl-4-phenylpyridinium (MPP+), apoptosis was prevented and a reduction in ROS was observed in cells overexpressing an active form of Akt (Salinas et al., 2001). Activation of Akt during acute cellular insults also appears to be necessary to foster cell survival. Phosphorylation of Akt has been observed in the brain following either focal or global cerebral ischemia (Friguls et al., 2001; Yano et al., 2001). Sublethal ischemic induction during preconditioning experiments leads to the phosphorylation of Akt in the hippocampal CA1 region. This activation of Akt was not present in ischemic animals that did not receive sublethal ischemic preconditioning and led to a greater degree of cerebral infarction, suggesting that Akt activation provides an important mechanism for ischemic preconditioning (Yano et al., 2001). Cell culture experiments also have supported that hypoxic preconditioning may be mediated by the activation of Akt (Wick et al., 2002).
sustain itself during adverse environments. In the following sections, we discuss novel downstream cellular pathways that are linked to neurodegenerative disorders that involve the Forkhead family of transcription factors, the glycogen synthase kinase-3b (GSK-3b), the cAMP-response elementbinding protein (CREB), Bad, IkB kinase (IKK), mitochondrial dysfunction, caspases, and calpains. Further knowledge of these processes may ultimately identify unique therapeutic strategies against oxidative stress that involve cellular metabolism, genomic DNA repair, metabotropic glutamate modulation, and cytokine activity. 8.1. The Forkhead transcription factors Three members of the mammalian Forkhead family have been identied and consist of the Forkhead in rhabdomyosarcoma (FKHR, also named as FOXO1), the FKHRL-like 1 (FKHRL1, FOXO3a), and the acute-lymphocytic-leukemia1 fused gene from chromosome X (AFX, also named as FOXO4). The Forkhead family is characterized by the Forkhead box or winged helix that contains a 110 amino acid binding domain. Upon activation such as during oxidative stress, the Forkhead family members are translocated to the nucleus. They function as transcription factors by preferentially binding to the core consensus DNA sequence 50 -TTGTTTAG-30 , the Forkhead response element. The cellular function of Forkhead family is broad and is involved in cell processes such as apoptotic injury (Gilley et al., 2003), cell cycle progression (Schmidt et al., 2002), oxidative stress (Kops et al., 2002), and the longevity of an organism (Taub et al., 1999). Modulation of activity of the Forkhead family has been closely associated with Akt (Fig. 1). Following activation, Akt can phosphorylate all three members of the Forkhead family resulting in their retention in the cytosol of cells and the subsequent blockade of their transcriptional activities. Three phosphorylation sites for Akt have been identied in all three members of Forkhead family. In FOXO1, the phosphorylation sites reside at Thr24, Ser256, and Ser319. In FOXO4, the sites include Thr28, Ser193, and Ser258. Among the three phosphorylation sites for FOXO3a that include Thr32, Ser253, and Ser315, Akt preferentially phosphorylates Ser253 (Brunet et al., 1999). Mutation of the Akt phosphoacceptor sites to alanine residues on FOXO can enhance the transcriptional activity of FOXO and render it resistant to Akt inhibition, suggesting that Akt requires these sites of phosphorylation to modulate the transcriptional activity of FOXO (Tang et al., 1999). The phosphorylation of the FOXO proteins results in their inactivation through cytoplasmic retention. In the absence of Akt activity or following the mutation of the FOXO phosphorylation sites, FOXO is exclusively localized to the nucleus. Translocation of FOXO also can occur during a cellular insult, such as in the presence of oxygen-glucose deprivation. Following Akt activation, Akt translocates to the nucleus in which Akt phosphorylates the FOXO
8. Downstream cellular targets At this point of time, no denitive therapy for either acute or chronic neurodegenerative diseases is available. Yet, investigations into the cellular pathways that determine oxidative stress and apoptotic injury have begun to elucidate pathways that provide us with a clearer understanding of the mechanisms that determine a cells ability to function and
221
transcription factor resulting in the export of FOXO into the cytosol. This translocation of FOXO by Akt is associated with protein 1433. The 1433 family of proteins function through binding to their protein ligands in a phosphorylation-dependent manner (Rena et al., 2001). Two binding motifs of 1433 proteins have been identied, namely RSXpSXP and RXY/FXpSXP (Yaffe et al., 1997), which are present in nearly all known 1433 proteins. The phosphorylation of FOXO transcription factors by Akt leads to the generation of consensus binding sites for the 14 33 protein and the subsequent export of FOXO from the nucleus. Akt inhibition of FOXO3a requires its phosphorylation that results in the association of FOXO3a with 143 3 protein and retention of FOXO3a in the cytoplasm, rendering it ineffective to target genes in the nucleus and thus blocking apoptosis. During periods of oxidative stress in the nervous system, an initial inhibitory phosphorylation of FOXO3a at the regulatory phosphorylation sites (Thr32 and Ser253) can occur (Chong et al., 2004c). However, loss of phosphorylated FOXO3a expression appears to subsequently result over a 12 h period, possibly by caspase degradation, which potentially can enhance the vulnerability of neurons to apoptotic injury during neurodegenerative disorders (Chong et al., 2004c). The transcriptional activity of the FOXO family is closely related to the induction of apoptosis. In the nucleus, FOXO can bind to specic DNA sequences and mediate the activation of transcription that plays essential roles in the regulation of cell survival. Expression of an Akt-resistant mutant of FOXO that promotes the activity of FOXO can lead to apoptosis (Tang et al., 1999). On the other hand, activation of Akt can lead to the inhibition of FOXO-dependent transcription and block of apoptosis (Brunet et al., 1999). FOXO3a can result in PCD in cerebral granule neurons, sympathetic neurons, and a variety of other cell types in a transcription-dependent manner following its translocation to the nucleus (Brunet et al., 1999; Dijkers et al., 2002; Gilley et al., 2003). Further work has demonstrated that activation of FOXO3a can disrupt mitochondrial membrane potential and result in cytochrome c release (Dijkers et al., 2002). Several transcriptional targets of FOXO in mammalian cells that are necessary for the induction of apoptosis have been identied. The death receptor Fas ligand appears to be an important target of FOXO. A Forkhead binding sequence is present in the regulatory region of the Fas ligand gene, suggesting that FOXO may control the expression of the endogenous Fas ligand gene. In addition, FOXO3a can activate a Fas ligand promoter-driven reporter and result in apoptosis in cerebellar neurons, broblasts, and Jurkat cells (Brunet et al., 1999). Yet, induction of apoptosis by a FOXO3a mutant that cannot be phosphorylated by Akt and would normally lead to cell injury can be blocked when expressed in Fas mutant or FADD (Fas-associated protein with death domain) mutant cells (Brunet et al., 1999), further suggesting that FOXO3a is dependent upon the Fas ligand for the generation of apoptosis.
FOXO also may promote apoptotic injury through the regulation of Bim. Bim, a BH3-only family member, functions upstream of Bax-mediated cytochrome c release from the mitochondria. Overexpression of FOXO3a has been reported to enhance Bim expression during cell stress such as trophic factor withdrawal and lead to PCD that requires Bim activity (Gilley et al., 2003). In addition, FOXO3a can activate the Bim promoter through two conserved FOXO binding sites. Mutation of these sites blocks Bim promoter activation (Gilley et al., 2003). Closely linked to cell survival and longevity is the control of the cell cycle by FOXO. FOXO controls the cell cycle through the increased expression of p27KIP1 (Medema et al., 2000) which can ultimately lead to PCD. p27KIP1 has been suggested to be critical in the regulation of cell survival, since even ectopic expression of p27KIP1 is sufcient to result in cellular apoptosis (Dijkers et al., 2000). p27KIP1 triggers apoptosis in several different human cancer cell lines. In human prostate carcinoma cells, a recombinant adenovirus expression of p27KIP1 is associated with the induction of apoptosis (Katner et al., 2002). In cholangiocarcinoma cell lines, overexpression of p27KIP1 leads to apoptosis that can be completely prevented by the neutralizing antibody of Fas ligand, suggesting that p27KIP1 induces apoptosis through Fas mediated pathways (Yamamoto et al., 2003). Furthermore, transfection of the full-length human p27 cDNA results in apoptotic cell death in retinoblastoma protein (Rb) expressing cells, but not in cells which do not express Rb, suggesting that some level of Rb expression is required for the induction of apoptosis by p27 (Naruse et al., 2000). FOXO3a results in a striking increase in p27KIP1 promoter activity with the induction of the apoptosis (Dijkers et al., 2000). New work has suggested that in cases in which the Sir2 homolog SIRT1 can form a complex with FOXO3 during oxidative stress, cell longevity is fostered rather than inhibited by promoting cell cycle arrest and preventing apoptosis (Brunet et al., 2004). In addition, FOXO appears to control cell survival through modulation of caspases. Fas-associated death domain-like interleukins 1b-converting enzyme (FLICE)like inhibitory protein (FLIP) is a homolog of caspase 8 and functions as a dominant-negative inhibitor of caspase 8. A recent study has demonstrated that transduction of active FOXO3a can result in the down-regulation of FLIP, an increase of caspase 8 activity, and the promotion of apoptosis in ECs (Skurk et al., 2004). In contrast, overexpression of a dominant-negative FOXO3a increased FLIP expression, down-regulated caspase 8 activity, and blocked apoptosis during serum deprivation (Skurk et al., 2004). Interestingly, caspase 3 also may be responsible for the degradation of FOXO3a. The integrity of FOXO may function as a signicant precipitant of cell injury. During periods of oxidative stress in the nervous system, an initial inhibitory phosphorylation of FOXO3a at the regulatory phosphorylation sites (Thr32 and Ser253) can occur (Chong et al., 2004c). However, loss of phosphorylated FOXO3a
222
expression appears to subsequently result over a 12 h period, possibly by caspase 3 cleavage, which potentially can enhance the vulnerability of cells to apoptotic injury (Chong et al., 2004c). FOXO3a proteolysis occurs during cell injury yielding an amino-terminal (Nt) fragment that can become biologically active (Charvet et al., 2003). During cell injury and caspase-dependent cleavage of FOXO3a, it is the activation of FOXO3a Nt fragments that become available and result in apoptotic cellular injury. 8.2. GSK-3b Glycogen synthase kinase-3 is a serine/threonine kinase that also is a substrate of Akt (Fig. 1). In mammalian cells, there are two GSK-3 isoforms termed GSK-3a and GSK-3b, which have a mass of 51 and 47 kDa, respectively. Of the two isoforms of GSK-3, GSK-3b is specically expressed in the CNS. GSK-3 is a constitutively active kinase in cells and is primarily regulated through inhibition of its activity. Akt can phosphorylate GSK-3b at Ser9 and inactivate the enzyme (Shaw et al., 1997). In contrast, phosphorylation of GSK-3b at Thr216 results in an enhanced activity of the enzyme, which can occur during neuronal degeneration (Bhat et al., 2000). GSK-3b plays a signicant role in the regulation of apoptosis. Apoptotic injury is enhanced by the overexpression of GSK-3b, suggesting that the activity of GSK-3b contributes to cellular injury (Crowder and Freeman, 2000). During oxidative stress, GSK-3b can lead to caspase 3 activation and cytochrome c release (Koh et al., 2003). In erythroid progenitors, the expression of a constitutively active mutant of GSK-3b during serum deprivation promotes cellular PCD (Somervaille et al., 2001). GSK-3b also can lead to apoptotic injury in vascular smooth muscle cells (Loberg et al., 2002) and cardiomyocytes (Yin et al., 2004). Yet, the inactivation of GSK-3b can result in the prevention or reduction in apoptotic injury in neurons (Alvarez et al., 1999), vascular smooth muscle cells (Loberg et al., 2002), and cardiomyocytes (Yin et al., 2004). GSK-3b is involved in the pathological process of neurodegenerative disorders, such as AD (Jope and Johnson, 2004; Maiese and Chong, 2004). In AD patients, GSK-3b expression is present in the cytoplasm of pre-tangle neurons and its expression coincides with the development of neurobrillary changes (Pei et al., 1999). On a cellular level, Ab exposure in cultured hippocampal neurons can activate GSK-3b (Takashima et al., 1998a). In addition, application of antisense oligonucleotides against GSK-3b and the GSK3b inhibitor, lithium, can prevent cellular injury mediated by Ab (Alvarez et al., 1999; Takashima et al., 1993). GSK-3b also can regulate APP processing and the phosphorylation of tau. GSK-3b facilitates Ab release by increasing the cellular maturation of APP (Aplin et al., 1997), a process believed to occur during the early onset of Alzheimers disease (Citron et al., 1994). GSK-3b is also one of the protein kinase candidates that can phosphorylate
the tau protein. Hyperphosphorylated tau is the major component of neurobrillary tangles that consist of paired helical laments. GSK-3b appears to be necessary for sequential phosphorylation of tau at sites that are required for the formation of a paired helical laments (ZhengFischhofer et al., 1998). Overexpression of GSK-3b in transgenic mice results in the hyperphosphorylation of tau in hippocampal neurons and pre-tangle-like somatodendritic localization of tau (Lucas et al., 2001). If one removes GSK3b activity through the inhibitor lithium, hyperphosphorylation of tau is blocked and tau binding to microtubules is promoted to yield microtubule assembly (Hong et al., 1997; Munoz-Montano et al., 1997). Point mutations in the presenilin-1 (PS1) gene and its gene product also have been tied to tau phosphorylation and GSK-3b activity. Mutations in PS1 account for approximately 50% of all cases of familial AD. PS1 is a 4348 kDa membrane bound protein with 68 membrane-spanning domains and is expressed in neurons throughout the brain (Maiese and Chong, 2004). Presenilin proteins that are mutated in AD are believed to accelerate the production of amyloid plaques as well as possibly activate apoptotic genes. In addition, mutations in PS1 are thought to promote the phosphorylation of tau through GSK-3b mediated pathways. PS1 can bind GSK-3b and tau at the same region of residues 250298 on the PS1 protein. Through this binding, PS1 may regulate the interaction of GSK-3b with tau by bringing them into close proximity (Takashima et al., 1998b). Point mutations of PS1 also have been shown to enhance the binding of PS1 to GSK-3b and result in increased phosphorylation of tau (Takashima et al., 1998b). GSK-3b mediates cellular survival through b-catenin, translation initiation factor 2B (eIF2B), c-Jun, and the cAMP-response element-binding protein (CREB). b-Catenin appears to be one of its important targets and may be relevant during both neuronal and vascular injury models. In many cell systems that include ECs and cancer cells, inhibition of apoptosis has been suggested to be regulated through the stabilization and activation of b-catenin (Chen et al., 2001; Wu et al., 2003). It has been demonstrated that loss of b-catenin signaling in neurons increases their vulnerability to apoptotic injury in the presence of Ab (Zhang et al., 1998). Furthermore, GSK-3b and PS1 may have an additional relationship through b-catenin. PS1 can promote the stability of b-catenin, a substrate of GSK-3b. GSK-3b negatively regulates b-catenin through phosphorylation and degradation. In the PS1 hydrophilic loop domain, three GSK-3b consensus phosphorylation sites are present that phosphorylate PS1 to abolish the ability of PS1 to stabilize and prevent the degradation of b-catenin (Kirschenbaum et al., 2001). b-Catenin also is a critical component of the Wnt signaling pathway (Chong and Maiese, 2004). Wnt can block the activity of GSK-3b by binding to the transmembrane receptor Frizzled and the co-receptor lipoprotein related proteins 5 and 6 (LRP-5/6) that lead to the
223
recruitment of disheveled, a cytoplasmic bridging molecule (Wehrli et al., 2000). In the absence of Wnt activity, GSK-3b phosphorylates b-catenin at serine or threonine residues of the N-terminal region to predispose degradation of b-catenin through ubiquination. GSK-3b dependent phosphorylation of b-catenin can be promoted through phosphorylation of Axin, a negative regulator of Wnt (Yamamoto et al., 1999). The eIF2B is another phosphorylation target of GSK-3b that is inhibited by phosphorylation. Activation of eIF2B can promote cell survival. Expression of eIF2B mutants in cells that lack GSK-3b phosphorylation or priming sites is sufcient to prevent apoptosis during GSK-3b overexpression, PI 3-K inhibition, or growth factor deprivation (Pap and Cooper, 2002). These mutations in eIF2B also can prevent cytochrome c release resulting from PI 3-K inhibition (Pap and Cooper, 2002), suggesting that eIF2B protects cells by functioning upstream of mitochondrial cytochrome c release. GSK-3 can lead to cell death through the expression of the c-Jun protein. c-Jun is a critical transcription factor in response to cellular stress. In neurons, c-Jun triggers apoptosis through transcription activation of some proapoptotic genes, such as Bim (Whiteld et al., 2001). An increase in c-Jun expression occurs during trophic factor withdrawal (Hongisto et al., 2003), administration of DNA damaging agents (Besirli and Johnson, 2003), or in the presence of low potassium (Yamagishi et al., 2003). Genetic deletion of c-Jun or application of neutralizing antibodies against c-Jun results in the resistance of neurons to apoptotic stimuli (Behrens et al., 1999; Watson et al., 1998), suggesting that c-Jun plays an important role in the generation of apoptosis. In vascular ECs, specic expression of c-Jun is sufcient for induction of apoptosis in ECs. Yet, overexpression of a dominant-negative mutant of c-Jun will attenuate hydrogen peroxide cell injury in ECs (Wang et al., 1999), indicating that c-Jun also is an important cell survival regulator in ECs. Given the roles that c-Jun plays in apoptosis, recent work has suggested that GSK-3 mediates PCD through the modulation of c-Jun activity. Application of indirubin, an inhibitor of GSK-3, can reduce c-Jun expression during trophic factor deprivation in cerebellar granule neurons. Similarly, the physiological inhibitor of GSK-3b, FRAT1 (frequently rearranged in advanced T-cell lymphoma type 1), also prevents c-Jun activity and blocks neuronal injury during trophic factor deprivation (Hongisto et al., 2003). The more specic inhibitor of GSK-3b, lithium, also has been shown to prevent both c-Jun expression and neuronal injury, suggesting that c-Jun is one of the executioners of GSK-3b to lead to apoptotic injury. In addition to b-catenin, eIF2B, and c-Jun, CREB also is as a transcriptional target of GSK-3b for the regulation of apoptosis. GSK-3b phosphorylates CREB at serine133 and serine129 to lead to CREB transcription and activation (Salas et al., 2003). CREB appears to have a dual role in the regulation of apoptosis. The involvement of CREB as a
protectant against PCD has been well documented in a variety of cell systems. In neurons, staurosporine induced apoptosis in neuroblastoma cells is accompanied by reduced levels of CREB (Francois et al., 2000). In contrast, overexpression of CREB can protect cell lines from okadaic acid-induced apoptosis (Walton et al., 1999). In addition, some growth factors can prevent neuronal apoptosis through CREB activation and the subsequent increase in Bcl-2 expression (Pugazhenthi et al., 1999). In vascular ECs, CREB also has been demonstrated to promote expression of human heme oxygenase-1, which is a potent regulator of inammation and can protect cells from oxidative stress (Kronke et al., 2003). On the other hand, CREB has been reported to promote apoptotic injury. In some cell systems and under specic experimental conditions, activation of CREB promotes the development of apoptosis. Activation of CREB can foster apoptotic injury in human microvascular ECs during 2,20 ,4,6,60 -penta-chlorobiphenyl administration (Lee et al., 2003). Furthermore, additional studies with human amnion FL cells, simian COS-7 cells, and Chinese hamster ovary cells illustrate that CREB overexpression can act to enhance apoptotic cell death (Saeki et al., 1999). 8.3. Bad, Bcl-xL, and NF-kB Bad is a Bcl-2 homology 3 (BH3)-only subfamily member of Bcl-2 proteins that are associated with the regulation of PCD. The activity of Bad is mediated through phosphorylation on its serine residues. Three phosphorylated serine sites have been identied on Bad, including serine112, serine136, and serine155. Serine112 can be phosphorylated by a number of kinases such as mitogenactivated protein kinase-activated protein kinase 1 (MAPKAP-K1), protein kinase A (PKA), and p21-activated kinase. Serine155 is phosphorylated by PKA while Akt preferentially phosphorylates the residue serine136 of Bad. A fourth phosphorylation site of Bad has recently been identied at serine170 that also results in the blockade of pro-apoptotic activity of Bad (Dramsi et al., 2002). The endogenous de-phosphorylated Bad is localized in the outer mitochondrial membrane and binds to the anti-apoptotic Bcl-2 family member Bcl-xL through its BH3 domain. Subsequent phosphorylation of Bad by Akt leads to the binding of Bad with the cytosolic protein 1433 to release Bcl-xL and allows it to block PCD (Li et al., 2001b). Bcl-2 and Bcl-xL prevent Bax translocation to the mitochondria, maintain the mitochondrial membrane potential, and prevent the release of cytochrome c from the mitochondria (Chong et al., 2003a; Putcha et al., 1999). Akt promotes cellular survival in many injury systems through its phosphorylation and inhibition of Bad (Fig. 1). Akt can block neuronal apoptosis that is mediated through the phosphorylation of Bad at serine136 (Datta et al., 1997). In addition, ectopic overexpression of constitutively active Akt increases the survival of adult rat ventricular myocytes
224
during hypoxia with reoxygenation and leads to the phosphorylation of Bad, suggesting that Akt phosphorylation of Bad is involved in cell survival mechanisms (Uchiyama et al., 2004). During hypoxia, activation of platelet-derived growth factor b in the dorsocaudal brain stem also has been shown to block apoptosis through Akt activation and the subsequent phosphorylation of Bad (Simakajornboon et al., 2001). The complement complex C5b-9 consisting of C5b, C6, C7, C8, and C9 proteins, which play a signicant role in the pathogenesis of neurodegenerative diseases, can protect oligodendrocytes from mitochondrial dysfunction, cytochrome c release, and caspase 3 activation (Soane et al., 2001). This protective capacity of C5b-9 is controlled through the combined activation of Akt with the phosphorylation of Bad, resulting in dissociation of Bad from the Bad/Bcl-xL complex (Soane et al., 2001). In the vascular system, activation of Akt and the direct inactivation of Bad can protect ECs from growth factor deprivation or oxidative stress (Chen et al., 2004; Chong et al., 2003b). In cell systems that have examined neoplastic growth, estradiol has been shown to prevent apoptosis in breast cancer cells through phosphorylation of Bad that is linked to Akt activation (Fernando and Wimalasena, 2004). Several Bcl-2 family members have been linked to cellular injury during chronic neurodegenerative disorders. Apoptotic injury as a result of Ab (142) administration is associated with an increase of Bax and caspase 3 activation (Koriyama et al., 2003). Furthermore, work that has infused Ab (140) into the cerebral ventricles of rats results in the up-regulation of Bax as well as the down-regulation of Bcl-2 in cortical and hippocampal regions bordering the lateral ventricle (Wang et al., 2001). Similarly, in primary human cultured neurons, application of Ab (142) produces sustained induction of Bax and a reduction in Bcl-2 expression (Paradis et al., 1996). Additional evidence for the ability of Bcl-2 proteins to modulate neuronal survival during AD is demonstrated with microinjection of a human cDNA expression construct of Bcl-2 that can block cell injury during Ab exposure (Zhang et al., 2002). Protection against oxidative stress also is dependent upon the activation of nuclear factor-kB (NF-kB) in conjunction with Akt (Fig. 2). Akt uses IkB kinase (IKK) and the IKKa catalytic subunit to efciently stimulate the transactivation domain of the p65 subunit of NF-kB. Once activated, NF-kB results in the induction of several anti-apoptotic genes. NFkB has been shown to induce the expression of the inhibitors of apoptotic protein (IAPs) c-IAP1, c-IAP2, and Xchromosome-linked IAP. IAPs can specically inhibit active forms of caspases 3, 7, and 9 (Reed, 2001). Induction of IAP1 and c-IAP2 by NF-kB also suppresses TNF-a initiated apoptosis through the inhibition of caspase 8 activation (Wang et al., 1998). In addition, XIAP activation by NF-kB is associated with the down-regulation of c-Jun-amino terminal kinase (JNK) (Tang et al., 2001). Growth arrest and DNA damage protein 45 (Gadd45b) also has been identied as another downstream target of NF-kB. Gadd45b is a
member of the Gadd45 family associated with cell cycle and DNA repair (Zhan et al., 1999). The induction of Gadd45b protein by TNF-a is NF-kB dependent and responsible for the down-regulation of JNK activation and suppression of apoptosis (De Smaele et al., 2001). NF-kB also may prevent apoptosis through the direct activation of Bcl-xL (Chen et al., 2000). 8.4. Mitochondrial dysfunction Mitochondria are vital organelles that play multiple roles in the cell which include amino acid biosynthesis, fatty acid oxidation, and steroid metabolism. More importantly, mitochondria maintain the cellular energy reserves with ATP production through the electron transport of the respiratory chain. Yet, recent work has linked mutations in the mitochondrial genome involving transfer RNA with the potential development of a host of disorders, such as hypertension, hypercholesterolemia, and hypomagnesemia (Wilson et al., 2004). Mitochondria are known to be a signicant source of superoxide radicals and other ROS that are associated with oxidative stress (Smeitink et al., 2004). Impairment of the electron transfer chain at the avin mononucleotide group of complex I (NADPH ubiquinone oxidoreductase) or at ubiquinone site of complex III (ubiquinone-cytochrome c reductase) results in the active generation of ROS. Once generated, ROS further impair mitochondrial electron transport and enhance ROS production (Smeitink et al., 2004). The permeability of the mitochondrial membrane is dependent upon the mitochondrial permeability transition pore (Bal-Price and Brown, 2000; Chong et al., 2003a; Lin et al., 2000). The mitochondrial permeability transition pore is a multi-protein complex that is located at the contact sites of the inner and the outer membrane, providing a free passage for ions and compounds with a molecular weight of 1.5 kDa or less. The mitochondrial permeability transition pore is formed at the contact between the inner mitochondrial membrane and the outer mitochondrial membrane and is composed of voltage-dependent anion channel (VDAC) in the outer membrane and the adenine nucleotide translocator (ANT) in the inner membrane. The opening of the mitochondrial permeability transition pore, which is regulated by mitochondrial membrane potential (DCm) (Bernardi, 1992), results in the release of cytochrome c from the mitochondria to the cytosol with the assistance of Bax translocation (Maciel et al., 2001). Oxidative stress directly leads to mitochondrial dysfunction (Fig. 3). During the generation of ROS, such as with the application of hydrogen peroxide in neurons, mitochondrial dysfunction results in cytochrome c release (Kirkland et al., 2002). In addition, generation of NO following anoxia in neurons or ECs also leads to the depolarization of the mitochondrial membrane and the subsequent release of cytochrome c (Lin and Maiese, 2001; Lin et al., 2000). In animal studies, cytochrome c release from mitochondria
225
Fig. 3. Oxidative stress leads to mitochondrial membrane depolarization. Mitochondrial membrane depolarization in cerebral microvascular endothelial cells (ECs) was imaged with a membrane potential indicator (JC-1 2 mg/mL, 30 min) 3 h following an 8 h period of oxygen-glucose deprivation (OGD). OGD in ECs was performed by replacing media with glucose-free HBSS containing 116 mM NaCl, 5.4 mM KCl, 0.8 mM MgSO4, 1 mM NaH2PO4, 0.9 mM CaCl2, and 10 mg/L phenol red (pH 7.4) and cultures were maintained in an anoxic environment (95% N2 and 5% CO2) at 37 8C for 8 h. When compared to untreated control mitochondria, exposure to OGD resulted in a signicant decrease in the red/green uorescence intensity ratio, suggesting that OGD results in mitochondrial membrane depolarization.
following cerebral ischemic-reperfusion injury can promote delayed neuronal death (Namura et al., 2001). Moreover, overexpression of copper/zinc SOD can attenuate mitochondrial oxidative injury and neuronal apoptosis after transient cerebral ischemia (Hayashi et al., 2003), suggesting that cell injury during ROS exposure is dependent upon mitochondrial dysfunction. Normally residing exclusively in the inner membrane space of mitochondria, cytochrome c, once released into the cytosol, binds to apoptotic protease-activating factor-1 (Apaf-1) leading to the caspase cascade activation. Apaf1 consists of three different domains that include a caspase recruitment domain (CARD), repeats of tryptophan and aspartate residues (WD-40 repeats), and a nucleotidebinding domain CED-4 (Zou et al., 1997). Binding of cytochrome c to Apaf-1 results in the removal of the WD-40 domain, which masks the CED-4 and CARD to prevent the binding of Apaf-1 to pro-caspase 9, leading to the oligomerization of Apaf-1 under the assistance of dATP/ ATP (Hu et al., 1999). Subsequently, the oligomerized Apaf1 recruits and activates caspase 9. In addition to cytochrome c, other mitochondrial proteins, such as endonuclease G (Li et al., 2001a), Smac/Diablo (Verhagen et al., 2000), and apoptosis-inducing factor (AIF) (Susin et al., 1999) also can be released in response to injury. Endonuclease G is recognized as a DNase responsible for DNA fragmentation during apoptosis. The caspase co-activator Smac/Diablo competes with caspase 9 for binding to the X-chromosomelinked inhibitor of apoptosis proteins (XIAPs) to block activities of these proteins. AIF translocates from the mitochondria to the nucleus to promote chromatin condensation and large-scale DNA fragmentation. The mitochondrial membrane permeability and the release of pro-apoptotic proteins are also regulated by Bcl-2 family proteins. Bcl-2 family is a group of proteins that regulate apoptosis through the modulation of mitochondrial homeostasis. Many Bcl-2 family members have been
identied and are functionally categorized into two groups: anti-apoptosis-members (Bcl-2, Bcl-xL) and pro-apoptosismembers (Bax, Bad, Bak, Bid, Mcl-2). Bcl-2 and Bcl-xL have been suggested to function through binding to proapoptotic proteins Bad, Bax and Bak. Bcl-xL prevents the depolarization of mitochondrial membrane potential and the production of ROS from mitochondria, therefore preventing apoptosis (Gottlieb et al., 2000). The loss of mitochondrial membrane potential by direct application of hydrogen peroxide also can be blocked by the overexpression of Bcl-2. These studies suggest that Bcl-2 and Bcl-xL function to maintain the integrity of mitochondrial membrane and inhibit the release of pro-apoptotic proteins from mitochondria. As a result, Bcl-2 and Bcl-xL block apoptosis by preventing mitochondrial cytochrome c release during oxidative stress in both neurons and ECs (Kowaltowski et al., 2000; Shimura et al., 2000). In contrast, once the proapoptotic member Bax is translocated to mitochondrial membrane from the cytosol, it forms homo-multimers and inserts into the mitochondrial membrane to facilitate cytochrome c release (Kowaltowski et al., 2000; Shimura et al., 2000). In addition, Bax has been demonstrated to increase the production of ROS from mitochondria (Kirkland et al., 2002). The anti-apoptotic function of Akt also may be mediated through the mitochondrial signaling. Akt may control mitochondrial release through the modulation of Bad. Bad is thought to induce apoptosis via the formation of heterodimers with Bcl-xL resulting in the displacement and release of Bax from the binding with Bcl-xL. Bax can then translocate to the mitochondria where it promotes cytochrome c release. Akt phosphorylates Bad, inhibits Bax conformational change, and blocks the translocation of Bax to the mitochondria preventing cytochrome c release and apoptosis (Yamaguchi et al., 2001). Alternatively, Akt may act directly at the level of the mitochondrial membrane and alter mitochondrial pore formation through pathways that
226
are independent from Bcl-xL. In some cell systems, Akt appears to rely on the maintenance of DCm to a greater degree than Bcl-xL to maintain cell survival and prevent cell injury (Plas et al., 2001). Additional work suggests that Akt prevents apoptotic injury through the direct modulation of the inner mitochondrial membrane potential (Dijkers et al., 2002), since Akt is ineffective in fostering cell survival during the direct application of cytochrome c (Kennedy et al., 1999). Investigations that have employed neuronal or EC clones to either overexpress the myristoylated (active) form of Akt or a dominant-negative Akt mutant that lacked kinase activity further support the premise that Akt directly maintains mitochondrial membrane potential and prevents the release of cytochrome c during oxidative stress injury (Chong et al., 2003b; Kang et al., 2003b). Cytokines, such as EPO, may modulate DCm and the release of cytochrome c directly or through the regulation of the Bcl-2 family member Bcl-xL. At least in erythroid cells, the Bcl-2 member Bcl-xL has been shown to be strongly expressed and necessary for EPO to prevent apoptosis in the later stages of erythroid progenitor cell life (Gregoli and Bondurant, 1997). In neurons, Bcl-xL has been shown to be strongly expressed during EPO administration (Wen et al., 2002). In addition, EPO may require Bcl-xL expression for cytoprotection, since without EPO, Bcl-xL is not expressed and apoptotic cell death results in hematopoietic cells (Silva et al., 1996). More recent work in cerebral ECs illustrates that up-regulation of Bcl-xL by EPO may be necessary for the prevention of PCD (Chong et al., 2003a; Maiese et al., 2005). Cellular energy metabolism is another signicant factor that controls mitochondrial membrane pore formation, since the maintenance of mitochondrial membrane potential is an ATP facilitated process (Lemeshko and Lemeshko, 2000). Studies with nicotinamide, a precursor for the coenzyme bnicotinamide adenine dinucleotide (NAD+) and an agent that prevents NAD+ depletion (Li et al., 2004b; Maiese and Chong, 2003), appear to support such a hypothesis. Nicotinamide can act directly at the level of mitochondrial membrane pore formation to prevent cytochrome c release (Chong et al., 2002d; Maiese and Chong, 2003; Maiese et al., 2001). Nicotinamide is able to reverse mitochondrial membrane depolarization (Chong et al., 2004c) during the induction of mitochondrial permeability transition pore formation by the agents tert-butylhydroperoxide, an oxidative inducer of mitochondrial membrane permeability that impairs mitochondrial ATP synthesis (Imberti et al., 1993), and during the administration of atractyloside, an agent that binds to the mitochondrial adenosine nucleotide translocator to elicit pore formation (Brown et al., 1997). In addition to its occurrence during acute cerebral ischemia, mitochondrial dysfunction has been observed during chronic neurodegenerative diseases. In AD, a decrease in the activity of the electron transport enzyme complex IV (cytochrome c oxidase) was found both in platelets and brain mitochondria (Cardoso et al., 2004; Kish
et al., 1999). The reduction of the subunit level of cytochrome c oxidase has been reported in degenerating brains areas, such as the temporal and the parietal cortices of AD patients (Kish et al., 1999). In patients with early AD, metabolic activity loss in the posterior cingulate cortex was signicantly greater than that in other brain regions (Minoshima et al., 1997), suggesting a functional alteration in the early progression of AD. Consistent with the hypometabolism in the posterior cingulated cortex, the activity of cytochrome c oxidase also was signicantly less in this region (Valla et al., 2001). Although the pathological function of the impairment of cytochrome c oxidase in AD requires further clarication, inhibition of cytochrome c oxidase activity has demonstrated to produce decits in maze learning and memory in animal models of AD (Bennett and Rose, 1992). Other components of AD may result in mitochondrial injury and increased permeability. In isolated mitochondria, application of Ab (2535), the cytotoxic fragment of Ab, opens the mitochondrial permeability transition pore and leads to the swelling of mitochondria. This process can be reversed by preventing the mitochondrial permeability transition pore opening through the specic inhibitor cyclosporin A (Bachurin et al., 2003). Further studies in brain mitochondria indicate that Ab induces cytochrome c release from mitochondria through the opening of the mitochondrial permeability transition pore (Kim et al., 2002; Rodrigues et al., 2000). Ab (2535) has been demonstrated to lead to the translocation of Smac from the mitochondria to the cytosol to bind to XIAPs, suggesting that Ab induction of apoptotic injury may be mediated through mitochondrial release of Smac and the subsequent loss of caspase inhibition (Yin et al., 2002a). In addition, Ab has been demonstrated to inhibit mitochondrial energy metabolism. Incubation of primary cortical neurons with Ab fragments results in the reduction of enzyme activities of the respiratory chain including complexes IIV. Accordingly, ATP concentration in neurons is reduced in response to Ab treatment (Casley et al., 2002). Mutations in presenilin 1 (PS1) also may affect mitochondrial membrane permeability. PS1 is primarily concentrated in cell bodies and the dendrites of neurons (Cook et al., 1996). In the subcellular compartments, PS1 is expressed not only in the endoplasmic reticulum (Kovacs et al., 1996) but also in the inner membrane of mitochondria (Ankarcrona and Hultenby, 2002). Mutations in the PS1 protein are associated with alterations of APP processing followed by the increased production of Ab (Qi et al., 2003). As a result of the increased Ab production through PS1, cells become hypersensitive to apoptotic stimuli (Chan et al., 2002). In synaptosomes from mice with PS1 mutations, mitochondrial membrane depolarization and caspase activation in response to Ab exposure have been demonstrated to be more severe when compared with synaptosomes from wild-type mice (Begley et al., 1999). Recently, PS1 associated protein (PSAP) has been proposed to be a pro-apoptotic mitochon-
227
drial protein (Xu et al., 2002). PSAP specically interferes with the function of PS1 through the interaction with the PS1 C-terminal. Overexpression of PSAP can promote the release of cytochrome c from mitochondria, result in caspase 3 activation, and lead to cellular apoptosis (Xu et al., 2002). These results suggest that intact PS1 potentially functions to protect cells from apoptosis through the modulation of mitochondrial membrane permeability. Oxidative damage in mitochondria has also been implicated in the pathogenesis of PD. In animal models of PD, application of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is metabolized to MPP+ that is sequestrated by mitochondria in neurons of the substantia nigra. MPP+ has been demonstrated to cause reversible inhibition of complex I of the electron transport chain resulting in the generation of oxygen free radicals and subsequent irreversible inhibition of complex I in mitochondria (Cleeter et al., 1992). In either in vitro or in vivo studies, MPTP also results in the neuronal generation of ROS and product of lipid peroxidation with delayed inhibition of complex I activity (Sriram et al., 1997). Furthermore, overexpression of copper zinc SOD in mice protects dopamine neurons against MPTP treatment (Przedborski et al., 1992), linking mitochondrial injury to ROS during PD. Mitochondrial injury also has been proposed in the pathogenesis of HD and ALS. In the autopsy brains of HD, the reduction of several mitochondrial enzyme activities has been observed. The activities of complexes IIIV of the mitochondrial electron transport chain have been shown to be reduced in the caudate and putamen in HD patients (Browne et al., 1997; Gu et al., 1996). In addition, inhibition of the mitochondrial electron transport by using 3nitropropionic acid and malonate results in similar pathological alterations and symptoms observed in HD (Beal et al., 1993; Borlongan et al., 1995). In regards to ALS, the skeletal muscle of the patients of sporadic ALS has been observed to have diminished levels (13 out of 17) or multiple deletions (one out of 17) of mitochondrial DNA (mtDNA) (Vielhaber et al., 2000). The decreased levels of membraneassociated mitochondrial MnSOD also was noted, suggesting that ROS-induced mtDNA damage may be of pathophysiological signicance in the etiology of sporadic ALS (Vielhaber et al., 2000). 8.5. Caspases Caspase activation has been identied as a hallmark of apoptosis. Caspases are a family of cysteine proteases that cleave their substrates after aspartic residues. They are usually synthesized as inactive zymogens that are proteolytically cleaved into subunits at the onset of apoptosis and function as active caspases after reconstitution to molecular heterodimers. Caspases are composed of three domains including an N-terminal prodomain, a large subunit, and a small subunit (Earnshaw et al., 1999). As a result of their activation sequence, caspases are classied as either initiator
caspases (also known as apical caspases) or effector caspases (Shi, 2004). An initiator caspase cleaves and subsequently activates an effector caspase. The apoptoticassociated caspases include initiator caspases, such as caspases 2, 8, 9, and 10, that activate downstream effector caspases, resulting in an amplication of cascade activity. The initiator caspases consist of long N-terminal prodomains that contain caspase recruitment domains (CARDs) in caspase 2 and caspase 9, or death effector domains (DEDs) in caspase 8 and caspase 10 (Hofmann et al., 1997). The effector caspases consist of caspases 3, 6, and 7 that function to directly cleave crucial cellular protein substrates that result in cell destruction. The effector caspases contain short prodomains or have no prodomains. Activation of caspases proceeds through extrinsic and intrinsic pathways. The extrinsic pathway is initiated by death receptor activation at the cell surface, resulting in the recruitment and activation of the initiator caspase 8 upon apoptotic stimuli (Ashkenazi and Dixit, 1998). The intracellular death domain of death receptors, such as the TNF superfamily, CD95/Fas/Apo-1, and the death receptor 3, undergoes conformational change upon binding to extracellular ligands and forms an intracellular deathinducing signaling complex following recruitment of adaptor molecules, such as the Fas-associated death domain (FADD). FADD recruits caspase 8 through its DED domain and this leads to caspase 8 activation (Juo et al., 1998; Varfolomeev et al., 1998). Caspase 8 can subsequently activate caspase 3. In addition, caspase 8 activation also may result in the cleavage of Bid, a pro-apoptotic member of Bcl2 family, allowing the truncated Bid (tBid) to translocate to the mitochondria (Li et al., 1998). This leads to cytochrome c release through Bax resulting in the subsequent activation of executioner caspases (Yin et al., 2002b). The intrinsic caspase pathway involves mitochondrial dysfunction. The mitochondrial pathway is associated with the release of cytochrome c and subsequent activation of caspase 9 followed by activation of caspase 3 (Liu et al., 1996). The process is regulated by the Bcl-2 subfamily BH3only proteins, which are normally located in cellular compartments other than mitochondria, but translocate to the mitochondria in response to apoptotic stimuli (Cosulich et al., 1997). The translocation of these proteins delivers an apoptotic signal to mitochondria through the interaction with Bax to induce the release of cytochrome c that then binds to Apaf-1. Apaf-1 consists of three different domains that include CARDs, repeats of tryptophan and aspartate residues (WD-40 repeats), and a nucleotide-binding domain CED-4. Binding of cytochrome c to Apaf-1 results in the removal of the WD-40 domain, masking the CED-4 and CARDs, and leads to the oligomerization of Apaf-1 with the requirement of dATP/ATP (Hu et al., 1999). The oligomerization of Apaf-1 promotes the allosteric activation of caspase 9 by forming the Apaf-1 apoptosome (Li et al., 1997a). Caspase 9 can subsequently activate caspase 3 (Li et al., 1997a) as well as caspase 1 through the intermediary
228
caspase 8 (Takahashi et al., 1999). Together, caspase 1 and caspase 3 lead to both DNA fragmentation and membrane PS exposure (Chong et al., 2002b; Li et al., 1997a; Maiese and Vincent, 2000). Modulation of caspase activation during oxidative stress can be critical in order to provide protection against PCD (Fig. 4). The caspases 1 and 3 have each been linked to the independent apoptotic pathways of genomic DNA cleavage and cellular membrane PS exposure (Chong et al., 2003a,e; Takahashi et al., 1999). These caspases, in addition to caspases 8 and 9, are also tied to the direct activation and proliferation of microglia (Chong et al., 2003b; Kang et al., 2003a,b). Caspase 1 is believed to be principally responsible for the externalization of membrane PS residues in several cell systems that can subsequently activate microglial phagocytosis (Maiese and Vincent, 2000; Vanags et al., 1996). Furthermore, caspase 9 is activated through a process that involves the cytochrome cApaf-1 complex (Chong et al., 2002c; Li et al., 1997a). In addition, caspase 8 serves as an upstream initiator of executioner caspases, such as caspase 3, and also leads to the mitochondrial release of cytochrome c (Engels et al., 2000; Stegh et al., 2002). Following caspase 8 and caspase 9 activation, caspase 3 directly leads to genomic DNA degradation.
Fig. 4. Oxidative stress leads to caspase and calpain activation. Oxidative stress results in mitochondrial dysfunction with the release of the proapoptotic proteins cytochrome c (Cyto c), endonuclease G (Endo G), Smac/ Diablo, and apoptosis-inducing factor (AIF). Cyto c plays critical role in the activation of caspases, which involves apoptotic protease-activating factor-1 (Apaf-1), caspase 9, caspase 3, and caspase 1. Endonuclease G is a DNase responsible for DNA fragmentation during apoptosis. The caspase coactivator Smac/Diablo blocks the activity of inhibitors of apoptotic protein (IAPs). AIF translocates from the mitochondria to the nucleus contributing to chromatin condensation and large-scale DNA fragmentation. Oxidative stress also can result in the activation of a death receptor, such as the Fas receptor (FasR). Coupled to the Fas ligand (FasL), FasR results in the recruitment of the adaptor protein, Fas-associated protein with death domain (FADD), to the receptor followed by caspase 8 activation. Caspase 8 can then activate caspase 3 and caspase 1, and cleave Bid. The truncated Bid (tBid) translocates to the mitochondria to trigger Cyto c release through the Bax-subfamily of Bcl-2 proteins. Calpains are also involved in caspase activation directly or through Bax-dependent pathways. Activation of caspases leads to both early cellular membrane phosphatidylserine (PS) exposure and late nuclear DNA fragmentation in the nucleus.
Caspase activation during ROS exposure has been closely associated to the pathogenesis of neurodegenerative disorders. One may predict that caspase activation would be a signicant factor for cellular injury during acute oxidative stress exposure, such as during cerebral ischemia (Benchoua et al., 2004), TBI (Clausen et al., 2004), ROS administration (Chong et al., 2002d; Maiese et al., 2000), and early retinal degenerative disease (Doonan and Cotter, 2004). Yet, what may be more interesting is the potential contribution of caspase activity during chronic neurodegeneration. Several studies support the belief that caspase activation is involved in the pathological process of chronic neurodegenerative diseases, such as AD. The elevation of caspase genes including caspases 13 and 59 has been observed in human postmortem brains from AD patients (Pompl et al., 2003). In addition, single neurons with DNA fragmentation have been shown to contain cytoplasmic immunoreactivity for active caspase 3, implying that apoptotic injury results during AD. In addition, activation of caspase 3 was found to occur in the parahippocampal gyrus in brains from patients with mild forms of AD. Caspase 3 immunoreactivity also was co-localized with paired helical laments in neurons, suggesting that caspase 3 activation may contribute to the formation of neurobrillary tangles (Gastard et al., 2003). This premise was further supported by a study that demonstrated the existence of fodrin caspase cleavage product in the hippocampus of AD patients, which was co-localized with neurobrillary tangles (Rohn et al., 2001). Additional work in cell culture experiments has demonstrated that treatment with Ab directly results in the activation of caspase 1 (Jordan et al., 1997), caspase 2, and caspase 3 (Troy et al., 2000). Caspase activation also is necessary for the processing of APP. Caspases cleave APP at three major caspase recognition sites, one at the C-terminus, D720, and two at the N-terminus, D197 and D219. Caspase activation results in the increased production of Ab. Yet, in some cases, Ab generation may not be entirely dependent upon the cleavage of APP at its C-terminal (D720) and/or N-terminal caspase sites. During etoposide-induced apoptosis ablation of caspase-dependent cleavage at D720, D197 and D219 (by site-directed mutagenesis) does not prevent enhanced Ab production (Tesco et al., 2003). It is conceivable that APP may lead to cell injury through a more direct route that involves the generation of the C-terminal fragment C31. Production of C31 is a result of APP cleavage at the caspase site D720 of the C-terminus. Following caspase 3 activation, caspase 3 generates the carboxyl-terminally truncated fragment C31 from APP, which has been shown to be capable of apoptotic injury independent of caspase 3 (Nishimura et al., 2002). Furthermore, caspase-dependent APP cleavage at D720 also has been observed in brains of AD patients through demonstration of C31 expression (Lu et al., 2000). Caspase processing of the tau protein and presenilins also may contribute to the pathology of AD. Cleavage of tau by
229
caspases can lead to the formation of intracellular neurobrillary tangles that are composed of the microtubule-associated protein tau during ROS exposure. Tau can be cleaved at Asp421 by caspases 1, 3, 7, and 8 resulting in the generation of a truncated tau protein (1421) that is more readily assembling into tau laments (Gamblin et al., 2003). The C-terminal peptide (422441) produced by caspase cleavage at Asp421 inhibits polymerization of the tau protein or the truncated tau protein (1421). Removal of the Cterminal peptide, an inhibitory control element, by caspase cleavage of tau enhances its polymerization and results in the formation of neurobrillary tangles (Berry et al., 2003). Both presenilin-1 (PS1) and presenilin-2 (PS2) are expressed in neurons throughout the brain and are primarily located in the endoplasmic reticulum, Golgi apparatus, nuclear envelope, cell membrane, and the inner membrane of mitochondria (Ankarcrona and Hultenby, 2002; Kovacs et al., 1996; Lah et al., 1997). The endoproteolytic cleavage of PS1 and PS2 yields 2735 kDa N-terminal fragments (NTFs) and 1524 kDa C-terminal fragments (CTFs). This cleavage of PS1 or PS2 can be prevented by blockade of caspase 1 or 3 activity or the mutation of caspase-cleave sites, such as Asp345/Ser346 for PS1 and Asp329/Ser330 for PS2 (Loetscher et al., 1997). Caspases 8 and 3 perform proteolysis on both PS1 and PS2, whereas caspases 1, 6, and 7 predominantly cleave PS2 (van de Craen et al., 1999). During apoptosis, cleavage of presenilins, such as PS1, may foster a cells demise. Overexpression of CTFs of PS2 promotes apoptosis by promoting Ab production, caspase 3 activity, cleavage of PARP, and loss of the anti-apoptotic protein Bcl-2 (Alves da Costa et al., 2003). 8.6. Calpains Calpains are part of an intracellular family of cysteine proteases that are independent from caspases. At least 15 mammalian calpains have been identied, with two of these calpains, calpain 1 (m-calpain) and calpain 2 (m-calpain), expressed primarily in the CNS. m-Calpain and m-calpain are heterodimeric proteins with a large 7080 kDa catalytic subunit and a 29 kDa regulated subunit. In the nervous system, m-calpain is predominantly distributed in dendrites and the bodies of neurons while m-calpain is expressed in axons and in glia (Onizuka et al., 1995). Calpain activation is initiated by calcium with limited autolysis (Moldoveanu et al., 2002). m-Calpain has a relatively high binding afnity to calcium and is activated by micromolar concentrations of calcium, while m-calpain binds to calcium with lower afnity and requires a higher concentration of calcium (millimolar) for activation (Matsumura et al., 2001; Pasquet et al., 1996; Shea, 1997). The activity of calpains also is regulated by the endogenous inhibitor calpastatin and the state of phosphorylation. For example, phosphorylation at Ser369 by protein kinase A (PKA) blocks the activation of m-calpain (Shiraha et al., 1999).
Calpains function not only as key regulators in cytoskeletal remodeling but also in initiating cell injury. Calpains cleave plasma-membrane-associated proteins, such as the epidermal growth factor receptor, the plateletderived growth factor receptor, and soluble kinases that include protein kinase C (Touyarot et al., 2000). In addition, cell structure can be modied through calpains through their substrates that involve the microtubule-associated proteins tau, neurolament, and actin (Banik et al., 1997; Potter et al., 1998). On the converse side, calpains can lead to cell injury through the induction of apoptotic pathways. For example, in neuronal cell lines, calpain activation was found to increase with an elevation in intracellular calcium during oxidative stress (Ishihara et al., 2000). Additional work has illustrated that free radical injury with associated mitochondrial dysfunction (Volbracht et al., 2001) as well as apoptotic injury following spinal cord trauma (Ray et al., 2003) could be prevented by calpain inhibition. Calpains function through a number of pathways in the apoptotic cascade. Bax, a member of the Bcl-2 family, has been identied as a target of calpain (Wood et al., 1998). The generation of pro-apoptotic 18 kDa fragment of Bax by calpain results in the induction of cytochrome c release, caspase 3 activation, and subsequent induction of apoptosis (Gao and Dou, 2000). Calpains also can directly modulate the activity of caspases (Fig. 4). m-Calpain cleaves caspase 3 producing a 29 kDa fragment, which further facilitates the subsequent cleavage of caspase 3 into active forms (Blomgren et al., 2001). In addition, calpain can directly activate caspase 7 and caspase 12 (Nakagawa et al., 2000; Ruiz-Vela et al., 1999). Although calpains may enhance caspase activity, calpains also can function to block the activation of caspases. Calpains can cleave caspase 9 rendering it incapable of activating caspase 3 and preventing the subsequent release of cytochrome c (Chua et al., 2000). The activation of calpains has been associated with ROS leading to apoptotic cellular injury. In neuronal cell lines, oxidative stress led to apoptotic morphological changes and DNA fragmentation that was accompanied by elevations in intracellular calcium and calpain activation (Ishihara et al., 2000). In other neuronal cell lines, treatment with hydrogen peroxide also resulted in the up-regulation of calpain activity and subsequent cellular apoptosis (Ray et al., 2000). Neuronal apoptosis in cerebellar granule cells during NO exposure also was shown to be mediated by calpain activation, since an inhibitor of calpain was able to block mitochondrial dysfunction and chromatin condensation (Volbracht et al., 2001). Protection with calpain inhibition has been extended to other acute injury paradigms and has been shown to prevent cellular PCD during spinal cord injury in the rat (Ray et al., 2003). The signicance of calpain activation during acute cerebral ischemia was demonstrated in early studies by the application of a cell permeable calpain inhibitor that signicantly attenuated ischemic brain injury (Hong et al., 1994). Subsequently, enhanced levels of intracellular
230
calpain activity was observed in hypoxic brain regions (Liebetrau et al., 1999), suggesting that calpain is a potential target for the treatment of ischemic stroke. Following TBI, the level of active form of m-calpain has also been shown to be increased in association with the accumulation of calpain mediated proteolytic products of a-spectrin (Kamp et al., 1996). Calpain inhibitors can prevent breakdown of neurolament and spectrin and reduce the traumatic brain injury (Posmantur et al., 1997), suggesting that inhibition of calpain activity can preserve the cytoskeletal structure of neurons during TBI. Application immediately post-injury of a calpain inhibitor also can signicantly attenuate experimental traumatic axonal injury (Buki et al., 2003). Given the broad function of calpains during both the maintenance of cellular cytoskeleton integrity and the induction of cell injury, it is not surprising that calpains also have a signicant role in the pathogenesis of neurodegenerative disorders. Calpain activation has been found in clinical brain specimens of AD (Taniguchi et al., 2001); calpain 2 was demonstrated to be present in approximately 75% of neurobrillary tangles (Adamec et al., 2002); and calpains may promote cell cycle activation, a potential source of cell injury in AD, through the activation of cyclindependent kinase 5 (Taniguchi et al., 2001). Further work has closely tied calpain activity to the toxicity of Ab and presenilins. In rat hippocampal neurons, calpain appears to be required for the induction of apoptosis during Ab application (Jordan et al., 1997). Overexpression of APP in neurons leads to calpain and caspase 3 activity, but activation of these pathways is lost in neurons that express an APP mutant defective in the Ab domain (Kuwako et al., 2002). In regards to presenilin activity, mutations in PS1 have been associated with increased activity of m-calpain and neuronal dysfunction (Chan et al., 2002), while mcalpain and m-calpain have been shown to regulate PS1 activity by cleaving this protein (Maruyama et al., 2000).
9. Future directions Therapeutic regimens for neurodegenerative disorders that seek to reduce or eliminate injury from ROS currently focus on a limited number of strategies. For example, prevention of N-methyl-D-aspartate (NMDA) receptor activity during memory loss associated with AD is considered to be one potential route for treatment. Although memantine, an antagonist of the NMDA receptor, can lead to cognitive improvement in patients with moderate to severe forms of AD (Reisberg et al., 2003), the mechanism of action for this agent is unclear and may not involve ROS reduction (Religa and Winblad, 2003). In addition, other agents that may reduce oxidative stress, such as nonsteroidal anti-inammatory agents (Aisen et al., 2003) for the treatment of either acute or chronic neurodegenerative disorders also are limited at present. Unfortunately, present therapies may provide only marginal symptomatic relief. As
we move forward in understanding the multiple mechanisms that may contribute to cellular injury during oxidative stress, new investigative avenues may provide not only attractive alternative therapies but also viable treatments to either prevent or conceivably reverse the course of the disease. Several unique pathways are now under consideration, which involve the modulation of brain temperature, cellular metabolic activity, regulation of attempted cell cycle induction in post-mitotic neurons, manipulation of the metabotropic glutamate system, and trophic factor and cytokine management. The temperature of the brain may signicantly impact the extent of acute neuronal and vascular injury during oxidative stress. In a variety of experimental models, it has been shown that hypothermia of the brain may reduce oxidative stress and promote cellular survival. During transient global ischemia, moderate brain hypothermia (30 8C) can provide functional protection from learning decits as well as neuronal injury (Green et al., 1992; Kwon et al., 1999). In experimental models involving focal cerebral ischemia, cellular protection during hypothermia has been associated with several parameters that involve the animal strain, the depth and duration of the hypothermia, the onset of hypothermia, and the occurrence of reperfusion following the ischemic insult. During transient ischemia in either spontaneously hypertensive (SHR) rats or Wistar rats, hypothermia was most effective if initiated prior to ischemic reperfusion. Yet, in Long-Evans rats, hypothermia was protective during initiation of hypothermia either prior to of following the ischemic insult. In addition, hypothermia during permanent cerebral ischemia was not effective in the SHR rats, but hypothermia did provide cellular protection in Wistar rats (Ren et al., 2004). Other studies suggest that delayed intraischemic or postischemic hypothermia can be protective (Kawai et al., 2000), but moderate hypothermia rather than mild hypothermia may be required to achieve signicant protection in either pre-treatment or posttreatment paradigms (Huh et al., 2000; Yager and Asselin, 1996). Several cellular pathways may be associated with the cytoprotective effects of hypothermia. Hypothermia has been demonstrated to reduce cerebral blood ow and maintain cellular energy reserves (Ibayashi et al., 2000), decrease the permeability of the bloodbrain barrier (Karibe et al., 1994), attenuate intracellular calcium accumulation (Bickler et al., 1995), and prevent the extracellular release of glutamate in the cortex (Huang et al., 1998). Furthermore, hypothermia can reduce superoxide anion production in both neurons and vascular cells (Maier et al., 2002) as well as prevent hydroxyl radical formation (Hashimoto et al., 2003a) during cerebral ischemia. At this time, clinical applications for hypothermia have been met with mixed results. Some trials have shown that during specic scenarios, such as in individuals successfully resuscitated from cardiac arrest following ventricular brillation (Hypothermia after Cardiac Arrest Study Group,
231
2002), in patients with coma after out-of-hospital cardiac arrest (Bernard et al., 2002), or in patients receiving combination therapy involving hypothermia (Damian et al., 2004), individuals can experience improved neurologic outcome and reduced mortality following treatment with hypothermia (Maiese, 2004). Yet, other work that has examined individuals with closed head injury did not demonstrate efcacy with hypothermia applied at 30 8C (Clifton et al., 2001). It is also important to note that approaches such as hypothermia that have been advocated for the treatment of TBI may be detrimental under some circumstances since hypothermia can reduce major enzymes responsible for ROS scavenging that include catalase, glutathione peroxidase, and SOD in a rat model of TBI (DeKosky et al., 2004). In addition, recent studies involving patients following cardiopulmonary resuscitation revealed potential deleterious effects of hypothermia treatment associated with renal impairment (Zeiner et al., 2004), suggesting that further extensive clinical work is required to assess the role of several parameters, such as onset, depth, and duration of hypothermia, that have been shown to be critically relevant in experimental models. The maintenance of cellular energy reserves independent of the brains temperature also may be vital for cellular survival. The coenzyme nicotinamide adenine dinucleotide (NAD+) is closely tied to cellular metabolism and genomic DNA repair (Li et al., 2004b; Maiese et al., 2001). During a cellular insult that affects DNA integrity, PARP catalyses the synthesis of poly(ADP-ribose) from its substrate NAD+, which stimulates the process of DNA repair (Satoh and Lindahl, 1992). Increased activation of PARP leads to an extensive turnover of NAD+ and a signicant reduction in NAD+ levels. This can trigger the loss of NAD+ and ATP, leading to the death of a cell. Furthermore, oxidative stress can trigger the opening of mitochondrial membrane permeability transition pore (Chong et al., 2003a; Di Lisa et al., 2001; Kang et al., 2003b; Lin et al., 2000) and subsequently result in the release of NAD+ from mitochondria (Di Lisa et al., 2001). During conditions of oxidative stress and energy depletion in neurons, poly(ADP-ribosylation) activation and loss of NAD+ stores in mitochondria have been shown to lead to apoptotic injury. Restoration of NAD+ content in mitochondria with liposomal NAD+ prevents neuronal injury (Du et al., 2003). Given the detrimental cellular ramications of NAD+ depletion, both acute and chronic neurodegenerative diseases have been linked to the loss of NAD+ stores. In particular, in patients with AD, PARP and poly(ADP-ribose) can be detected in the frontal and temporal cortex more frequently than in controls, suggesting that increased levels of functional PARP enzyme are present to result in a signicant consumption of NAD+ stores (Love et al., 1999). In addition, a limited pilot study suggested that administration of nicotinamide adenine dinucleotide (NADH) in patients with AD may show improvement in their cognitive function (Birkmayer, 1996).
Yet, one must approach restorative therapy for NAD+ with caution, since activation of the NAD+ precursor nicotinamide can precipitate cellular aging (Li et al., 2004b). In fact, recent work that employs transcriptional proling of the human frontal cortex in the ageing brain suggests that altered expression of a variety of genes may promote oxidative stress, DNA damage, and impaired mitochondrial function (Lu et al., 2004). If one examines the aging process on more specic cellular terms, agents such as nicotinamide, an NAD+ precursor that is intimately tied to cell survival during acute apoptotic injury (Chong et al., 2004c; Li et al., 2004b; Maiese and Chong, 2003; Maiese et al., 2001), may negatively inuence the lifespan of cells through the regulation of the Sir2 gene (Lin and Guarente, 2003). The Sir2 gene belongs to a family of genes which is a highly conserved group in the genomes of organisms ranging from archaebacteria to eukaryotes (Frye, 2000; Vaziri et al., 2001). Interestingly, SIRT1 (Sir2a), as a human homolog of Sir2, is intimately linked with the modulation of cellular apoptotic pathways. The Sir2 protein is associated with nicotinamide and pyrazinamidase/nicotinamidase 1 (PNC1), an enzyme that deaminates nicotinamide. Nicotinamide appears to be capable of decreasing cell longevity through Sir2. Nicotinamide blocks cellular Sir2 by intercepting an ADP-ribosyl-enzyme-acetyl peptide intermediate with the regeneration of NAD+ (transglycosidation) (Jackson et al., 2003). Physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro, suggesting that nicotinamide is a physiologically relevant regulator of Sir2 enzymes (Bitterman et al., 2002). Alternative concepts for the prevention of oxidative stress may focus on the prevention of intracellular nicotinamide accumulation. During nicotinamide depletion, Sir2 is activated and employs PNC1 to regulate cell longevity. Increased expression of PNC1 has been found to be both necessary and sufcient for lifespan extension during calorie restriction in Saccharomyces cerevisiae (Anderson et al., 2003). Nicotinamide and PCN1 are closely linked in controlling cell life span. PNC1 can stimulate Sir2 histone deactylase activity by preventing the accumulation of nicotinamide through its conversion to nicotinic acid in the NAD+ salvage pathway. Overexpression of PNC1 has been demonstrated to suppress the inhibitory effect of exogenous nicotinamide on silencing, life span, and transcriptional repression of Sir2. As a result, PNC1 can positively regulate Sir2-mediated silencing and longevity by preventing the accumulation of intracellular nicotinamide (Gallo et al., 2004). Although signicant further work is required to link these studies to higher organisms, it is possible that nicotinamide may control similar processes during neurodegenerative disorders. Current interest also has focused on the protective role of the metabotropic glutamate receptors (mGluR) system. mGluR activation prevents, and in some cases, reverses genomic DNA degradation (Vincent et al., 1997), modulates endonuclease activation (Vincent et al., 1999), and main-
232
tains cellular membrane asymmetry (Vincent and Maiese, 2000). Cytoprotection by the mGluR system is believed to act at or below the level of free radical generation and oxidative stress (Maiese et al., 1996; Sagara and Schubert, 1998; Vincent et al., 1997). More recent work has suggested that the mGluR offers similar protective capacity to the vascular system by preventing endothelial cell DNA degradation, caspase activity, and inhibiting a thrombotic state through the maintenance of membrane asymmetry (Chong et al., 2003d; Lin et al., 2002; Lin and Maiese, 2001). During chronic neurodegenerative disease, a downregulation of mGluR binding sites has been reported (Dewar et al., 1991). Other studies illustrate that group I mGluRs can regulate the metabolism of APP and accelerate the processing of APP into non-amyloidogenic APP in AD (Lee et al., 1996). Activation of group I/II mGluRs can enhance the secretion of APP (Jolly-Tornetta et al., 1998). The process is blocked by the administration of ()-amethyl-4-carboxyphenylglycine, a non-selective antagonist of group I/II mGluRs (Ulus and Wurtman, 1997). Activation of group III mGluRs also has been shown to protect neurons against microglial neurotoxicity during Ab application (Taylor et al., 2003) that may be a result of the regulation of caspase activity (Chong et al., 2003d; Lin and Maiese, 2001). Under some circumstances, diminished activity of mGluRs may prove useful for cellular protection. Inhibition of group II mGluRs can attenuate microglial activation and subsequent neurotoxicity during toxic stimuli such as chromogranin A (Taylor et al., 2003), a protein up-regulated in AD. mGluRs also are believed to be necessary for the processing of learning and memory (Riedel et al., 1996). Cytokines and trophic factors may be another viable option that can specically target cellular pathways of oxidative stress. Cytokines that were previously thought to have no role in the brain, such as EPO, may have new applications targeted against ROS in the brain (Maiese et al., 2004, 2005). EPO is currently approved by the Food and Drug Administration for the treatment of anemia that can be the result of a variety of conditions. Yet, in just the brief span of approximately a decade, the premise that EPO is required only for erythropoiesis has been advanced by studies demonstrating the existence of EPO and its receptor in other organs and tissues outside of the liver and the kidney, such as the brain and heart. As a result, EPO has been identied as a possible candidate in the formulation of therapeutic strategies for both cardiac and nervous system diseases. Outside of the nervous system, EPO appears to be efcacious during cardiac ischemia and reperfusion injury (Li et al., 2004a; Maiese et al., 2005). EPO administration either prior to or during myocardial ischemia/reperfusion can protect against myocardial cell apoptosis and decrease infarct size, resulting in enhanced cardiac function and improved left ventricular contractility (Parsa et al., 2004). In addition to the correction of anemia, EPO can promote microvascular growth in the heart, suggesting that functional
cardiac recovery with EPO may ensue also from the generation of new blood vessels (Ribatti et al., 1999). Other experimental studies have illustrated a potential direct protection of myocardial cells during EPO administration that can increase cardiac cell proliferation in neonatal rats, reduce myocardiocyte apoptosis during ischemia-reperfusion injury, and improve left ventricular function (Moon et al., 2003; Parsa et al., 2003). More current clinical investigations involving subcutaneous EPO in diabetics and non-diabetics with severe, resistant congestive heart failure have shown to decrease breathlessness and/or fatigue, increase left ventricular ejection fraction, and signicantly decrease the number of hospitalization days (Silverberg et al., 2003). In patients with moderate to severe chronic heart failure, the peak oxygen consumption and exercise duration of patients are signicantly increased following treatment with EPO, suggesting that EPO can enhance exercise capacity in patients with heart failure (Mancini et al., 2003). In the nervous system, both cell culture and animal model work have demonstrated neuronal and vascular protection with EPO (Chong et al., 2002a,c; Genc et al., 2004). Studies with cerebral ventricular application of EPO during cerebral hypoxia-ischemia illustrate a reduction in ischemia-induced learning disability, increased neuronal survival, and the development of ischemic tolerance (Kumral et al., 2004; Ruscher et al., 2002). A number of additional studies have pursued systemic administration of EPO, since ventricular delivery systems are considered impractical for clinical applications. Systemic administration of EPO before or immediately after a retinal insult can protect retinal ganglion cells from apoptosis (Grimm et al., 2002) and can improve functional outcome and reduce lipid peroxidation during spinal cord injury (Kaptanoglu et al., 2004). Application of systemic EPO following experimental subarachnoid hemorrhage regulates the autoregulation of cerebral blood ow, reverses basilar artery vasoconstriction, and enhances neuronal survival and functional recovery (Olsen, 2003). Furthermore, EPO can block microglial cell activation and proliferation to prevent phagocytosis of injured cells through pathways that involve cellular membrane PS exposure, Akt (Chong et al., 2004a), and the regulation of caspases (Chong et al., 2003b,e). EPO can directly address cellular inammation by inhibiting several proinammatory cytokines, such as IL-6, TNF-a, and monocyte chemoattractant protein 1 (Chong et al., 2002c; Genc et al., 2004). It is clear that the cellular pathways responsible for apoptotic injury during oxidative stress are complex in nature. Yet, oxidative stress with the generation of ROS plays a critical role during cell dysfunction and cell demise in a number of neurodegenerative disorders that may be acute in nature, such as stroke, or more sub-acute in duration, such as AD, HD, and ALS. Central to cellular integrity and phagocytic disposal of injured cells are the
233
proto-oncogene Wnt and the serinethreonine kinase Akt that orchestrate closely aligned cellular pathways that involve components such as inammatory cytokines, glycogen synthase kinase-3b, Bad, Bcl-xL, caspase activation, and calpain regulation. With further work and insight into the cellular mechanisms responsible for oxidative stress injury, efcient and safe translation of these pathways into novel therapeutic mechanisms against neurodegenerative disorders will eventually allow clinical research to become more practice than promise.
Acknowledgments This work was supported by the following grants (KM): American Heart Association (National), Janssen Neuroscience Award, Johnson and Johnson Focused Investigator Award, LEARN Foundation Award, MI Life Sciences Challenge Award, and NIH NIEHS (P30 ES06639).
References
Adamec, E., Mohan, P., Vonsattel, J.P., Nixon, R.A., 2002. Calpain activation in neurodegenerative diseases: confocal immunouorescence study with antibodies specically recognizing the active form of calpain 2. Acta Neuropathol. (Berl.) 104, 92104. Adams, S., Green, P., Claxton, R., Simcox, S., Williams, M.V., Walsh, K., Leeuwenburgh, C., 2001. Reactive carbonyl formation by oxidative and non-oxidative pathways. Front. Biosci. 6, A17A24. Aisen, P.S., Schafer, K.A., Grundman, M., Pfeiffer, E., Sano, M., Davis, K.L., Farlow, M.R., Jin, S., Thomas, R.G., Thal, L.J., 2003. Effects of rofecoxib or naproxen vs. placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 28192826. Alam, Z.I., Daniel, S.E., Lees, A.J., Marsden, D.C., Jenner, P., Halliwell, B., 1997. A generalised increase in protein carbonyls in the brain in Parkinsons but not incidental Lewy body disease. J. Neurochem. 69, 13261329. Altomare, D.A., Guo, K., Cheng, J.Q., Sonoda, G., Walsh, K., Testa, J.R., 1995. Cloning, chromosomal localization and expression analysis of the mouse Akt2 oncogene. Oncogene 11, 10551060. Alvarez, A., Munoz, J.P., Maccioni, R.B., 2001. A Cdk5-p35 stable complex is involved in the beta-amyloid-induced deregulation of Cdk5 activity in hippocampal neurons. Exp. Cell Res. 264, 266274. Alvarez, G., Munoz-Montano, J.R., Satrustegui, J., Avila, J., Bogonez, E., Diaz-Nido, J., 1999. Lithium protects cultured neurons against betaamyloid-induced neurodegeneration. FEBS Lett. 453, 260264. Alves da Costa, C., Mattson, M.P., Ancolio, K., Checler, F., 2003. The Cterminal fragment of presenilin 2 triggers p53-mediated staurosporineinduced apoptosis, a function independent of the presenilinase-derived N-terminal counterpart. J. Biol. Chem. 278, 1206412069. Anderson, R.M., Bitterman, K.J., Wood, J.G., Medvedik, O., Sinclair, D.A., 2003. Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423, 181185. Ankarcrona, M., Hultenby, K., 2002. Presenilin-1 is located in rat mitochondria. Biochem. Biophys. Res. Commun. 295, 766770. Aplin, A.E., Jacobsen, J.S., Anderton, B.H., Gallo, J.M., 1997. Effect of increased glycogen synthase kinase-3 activity upon the maturation of the amyloid precursor protein in transfected cells. Neuroreport 8, 639 643. Arendt, T., Holzer, M., Stobe, A., Gartner, U., Luth, H.J., Bruckner, M.K., Ueberham, U., 2000. Activated mitogenic signaling induces a process of
dedifferentiation in Alzheimers disease that eventually results in cell death. Ann. NY Acad. Sci. 920, 249255. Arispe, N., Pollard, H.B., Rojas, E., 1993. Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(140)] in bilayer membranes. Proc. Natl. Acad. Sci. U.S.A. 90, 1057310577. Arur, S., Uche, U.E., Rezaul, K., Fong, M., Scranton, V., Cowan, A.E., Mohler, W., Han, D.K., 2003. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment. Develop. Cell 4, 587598. Ashkenazi, A., Dixit, V.M., 1998. Death receptors: signaling and modulation. Science 281, 13051308. Awasthi, D., Church, D.F., Torbati, D., Carey, M.E., Pryor, W.A., 1997. Oxidative stress following traumatic brain injury in rats. Surg. Neurol. 47, 575581, discussion 581582. Bachurin, S.O., Shevtsova, E.P., Kireeva, E.G., Oxenkrug, G.F., Sablin, S.O., 2003. Mitochondria as a target for neurotoxins and neuroprotective agents. Ann. NY Acad. Sci. 993, 334344, discussion 345349. Bal-Price, A., Brown, G.C., 2000. Nitric-oxide-induced necrosis and apoptosis in PC12 cells mediated by mitochondria. J. Neurochem. 75, 1455 1464. Banik, N.L., Matzelle, D., Gantt-Wilford, G., Hogan, E.L., 1997. Role of calpain and its inhibitors in tissue degeneration and neuroprotection in spinal cord injury. Ann. NY Acad. Sci. 825, 120127. Basso, A.D., Solit, D.B., Chiosis, G., Giri, B., Tsichlis, P., Rosen, N., 2002. Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J. Biol. Chem. 277, 3985839866. Basso, M., Giraudo, S., Corpillo, D., Bergamasco, B., Lopiano, L., Fasano, M., 2004. Proteome analysis of human substantia nigra in Parkinsons disease. Proteomics. Bayir, H., Kagan, V.E., Tyurina, Y.Y., Tyurin, V., Ruppel, R.A., Adelson, P.D., Graham, S.H., Janesko, K., Clark, R.S., Kochanek, P.M., 2002. Assessment of antioxidant reserves and oxidative stress in cerebrospinal uid after severe traumatic brain injury in infants and children. Pediatr. Res. 51, 571578. Bazan, N.G., Palacios-Pelaez, R., Lukiw, W.J., 2002. Hypoxia signaling to genes: signicance in Alzheimers disease. Mol. Neurobiol. 26, 283 298. Beal, M.F., Brouillet, E., Jenkins, B.G., Ferrante, R.J., Kowall, N.W., Miller, J.M., Storey, E., Srivastava, R., Rosen, B.R., Hyman, B.T., 1993. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 13, 41814192. Becker, E.B., Bonni, A., 2004. Cell cycle regulation of neuronal apoptosis in development and disease. Prog. Neurobiol. 72, 125. Beere, H.M., Wolf, B.B., Cain, K., Mosser, D.D., Mahboubi, A., Kuwana, T., Tailor, P., Morimoto, R.I., Cohen, G.M., Green, D.R., 2000. Heatshock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. 2, 469475. Begley, J.G., Duan, W., Chan, S., Duff, K., Mattson, M.P., 1999. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J. Neurochem. 72, 1030 1039. Behl, C., Davis, J.B., Lesley, R., Schubert, D., 1994. Hydrogen peroxide mediates amyloid beta protein toxicity. Cell 77, 817827. Behrens, A., Sibilia, M., Wagner, E.F., 1999. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat. Genet. 21, 326329. Bellacosa, A., Chan, T.O., Ahmed, N.N., Datta, K., Malstrom, S., Stokoe, D., McCormick, F., Feng, J., Tsichlis, P., 1998. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17, 313325. Benchoua, A., Braudeau, J., Reis, A., Couriaud, C., Onteniente, B., 2004. Activation of proinammatory caspases by cathepsin B in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 24, 12721279. Bennett, M.C., Rose, G.M., 1992. Chronic sodium azide treatment impairs learning of the Morris water maze task. Behav. Neural. Biol. 58, 7275.
234
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 p53, ICE-like proteases and the mitochondrial permeability transition. J. Cell Biochem. 66, 245255. Browne, S.E., Bowling, A.C., MacGarvey, U., Baik, M.J., Berger, S.C., Muqit, M.M., Bird, E.D., Beal, M.F., 1997. Oxidative damage and metabolic dysfunction in Huntingtons disease: selective vulnerability of the basal ganglia. Ann. Neurol. 41, 646653. Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J., Greenberg, M.E., 1999. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857868. Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., Hu, L.S., Cheng, H.L., Jedrychowski, M.P., Gygi, S.P., Sinclair, D.A., Alt, F.W., Greenberg, M.E., 2004. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 20112015. Buki, A., Farkas, O., Doczi, T., Povlishock, J.T., 2003. Preinjury administration of the calpain inhibitor MDL-28170 attenuates traumatically induced axonal injury. J. Neurotrauma 20, 261268. Busser, J., Geldmacher, D.S., Herrup, K., 1998. Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimers disease brain. J. Neurosci. 18, 28012807. Cagnin, A., Brooks, D.J., Kennedy, A.M., Gunn, R.N., Myers, R., Turkheimer, F.E., Jones, T., Banati, R.B., 2001. In vivo measurement of activated microglia in dementia. Lancet 358, 461467. Cai, Z., Manalo, D.J., Wei, G., Rodriguez, E.R., Fox-Talbot, K., Lu, H., Zweier, J.L., Semenza, G.L., 2003. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemiareperfusion injury. Circulation 108, 7985. Cardoso, S.M., Proenca, M.T., Santos, S., Santana, I., Oliveira, C.R., 2004. cytochrome c oxidase is decreased in Alzheimers disease platelets. Neurobiol. Aging 25, 105110. Carey, M.E., Tutton, R.H., Strub, R.L., Black, F.W., Tobey, E.A., 1984. The correlation between surgical and CT estimates of brain damage following missile wounds. J. Neurosurg. 60, 947954. Carver, D.J., Aman, M.J., Ravichandran, K.S., 2000. SHIP inhibits Akt activation in B cells through regulation of Akt membrane localization. Blood 96, 14491456. Casley, C.S., Land, J.M., Sharpe, M.A., Clark, J.B., Duchen, M.R., Canevari, L., 2002. Beta-amyloid fragment 2535 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol. Dis. 10, 258 267. Cernak, I., Savic, V.J., Kotur, J., Prokic, V., Veljovic, M., Grbovic, D., 2000. Characterization of plasma magnesium concentration and oxidative stress following graded traumatic brain injury in humans. J. Neurotrauma 17, 5368. Chan, S.L., Culmsee, C., Haughey, N., Klapper, W., Mattson, M.P., 2002. Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12. Neurobiol. Dis. 11, 219. Charvet, C., Alberti, I., Luciano, F., Jacquel, A., Bernard, A., Auberger, P., Deckert, M., 2003. Proteolytic regulation of Forkhead transcription factor FOXO3a by caspase-3-like proteases. Oncogene 22, 45574568. Chen, C., Edelstein, L.C., Gelinas, C., 2000. The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol. Cell Biol. 20, 26872695. Chen, J.H., Hsiao, G., Lee, A.R., Wu, C.C., Yen, M.H., 2004. Andrographolide suppresses endothelial cell apoptosis via activation of phosphatidyl inositol-3-kinase/Akt pathway. Biochem. Pharmacol. 67, 13371345. Chen, S., Guttridge, D.C., You, Z., Zhang, Z., Fribley, A., Mayo, M.W., Kitajewski, J., Wang, C.Y., 2001. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor-mediated transcription. J. Cell Biol. 152, 8796. Chen, T., Yang, I., Irby, R., Shain, K.H., Wang, H.G., Quackenbush, J., Coppola, D., Cheng, J.Q., Yeatman, T.J., 2003. Regulation of caspase expression and apoptosis by adenomatous polyposis coli. Cancer Res. 63, 43684374.
Bennett, D.A., Wilson, R.S., Schneider, J.A., Evans, D.A., Beckett, L.A., Aggarwal, N.T., Barnes, L.L., Fox, J.H., Bach, J., 2002. Natural history of mild cognitive impairment in older persons. Neurology 59, 198205. Benzing, W.C., Wujek, J.R., Ward, E.K., Shaffer, D., Ashe, K.H., Younkin, S.G., Brunden, K.R., 1999. Evidence for glial-mediated inammation in aged APP(SW) transgenic mice. Neurobiol. Aging 20, 581589. Bernard, S.A., Gray, T.W., Buist, M.D., Jones, B.M., Silvester, W., Gutteridge, G., Smith, K., 2002. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346, 557563. Bernardi, P., 1992. Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore by the proton electrochemical gradient. Evidence that the pore can be opened by membrane depolarisation. J. Biol. Chem. 267, 88348839. Berry, R.W., Abraha, A., Lagalwar, S., LaPointe, N., Gamblin, T.C., Cryns, V.L., Binder, L.I., 2003. Inhibition of tau polymerization by its carboxyterminal caspase cleavage fragment. Biochemistry 42, 83258331. Besirli, C.G., Johnson Jr., E.M., 2003. JNK-independent activation of c-Jun during neuronal apoptosis induced by multiple DNA-damaging agents. J. Biol. Chem. 278, 2235722366. Bhat, R.V., Shanley, J., Correll, M.P., Fieles, W.E., Keith, R.A., Scott, C.W., Lee, C.M., 2000. Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3-beta in cellular and animal models of neuronal degeneration. Proc. Natl. Acad. Sci. U.S.A. 97, 1107411079. Bickler, P.E., Buck, L.T., Feiner, J.R., 1995. Volatile and intravenous anesthetics decrease glutamate release from cortical brain slices during anoxia. Anesthesiology 83, 12331240. Birkmayer, J.G., 1996. Coenzyme nicotinamide adenine dinucleotide: new therapeutic approach for improving dementia of the Alzheimer type. Ann. Clin. Lab. Sci. 26, 19. Bitterman, K.J., Anderson, R.M., Cohen, H.Y., Latorre-Esteves, M., Sinclair, D.A., 2002. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 4509945107. Blomgren, K., Zhu, C., Wang, X., Karlsson, J.O., Leverin, A.L., Bahr, B.A., Mallard, C., Hagberg, H., 2001. Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of pathological apoptosis? J. Biol. Chem. 276, 1019110198. Bogdanov, M.B., Andreassen, O.A., Dedeoglu, A., Ferrante, R.J., Beal, M.F., 2001. Increased oxidative damage to DNA in a transgenic mouse model of Huntingtons disease. J. Neurochem. 79, 12461249. Bogdanov, M.B., Ramos, L.E., Xu, Z., Beal, M.F., 1998. Elevated hydroxyl radical generation in vivo in an animal model of amyotrophic lateral sclerosis. J. Neurochem. 71, 13211324. Boland, B., Campbell, V., 2003. Beta-amyloid (140)-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of polyADP-ribose polymerase. Neurobiol. Aging 24, 179186. Borlongan, C.V., Koutouzis, T.K., Freeman, T.B., Cahill, D.W., Sanberg, P.R., 1995. Behavioral pathology induced by repeated systemic injections of 3-nitropropionic acid mimics the motoric symptoms of Huntingtons disease. Brain Res. 697, 254257. Bornemann, K.D., Wiederhold, K.H., Pauli, C., Ermini, F., Stalder, M., Schnell, L., Sommer, B., Jucker, M., Staufenbiel, M., 2001. A betainduced inammatory processes in microglia cells of APP23 transgenic mice. Am. J. Pathol. 158, 6373. Bose, J., Gruber, A.D., Helming, L., Schiebe, S., Wegener, I., Hafner, M., Beales, M., Kontgen, F., Lengeling, A., 2004. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J. Biol. 3, 15. Brodbeck, D., Hill, M.M., Hemmings, B.A., 2001. Two splice variants of protein kinase B gamma have different regulatory capacity depending on the presence or absence of the regulatory phosphorylation site serine 472 in the carboxyl-terminal hydrophobic domain. J. Biol. Chem. 276, 2955029558. Brown, J., Higo, H., McKalip, A., Herman, B., 1997. Human papillomavirus (HPV) 16 E6 sensitizes cells to atractyloside-induced apoptosis: role of
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Chong, Z.Z., Maiese, K., 2004. Targeting WNT, protein kinase B, and mitochondrial membrane integrity to foster cellular survival in the nervous system. Histol. Histopathol. 19, 495504. Chong, Z.Z., Kang, J.Q., Maiese, K., 2002a. Angiogenesis and plasticity: role of erythropoietin in vascular systems. J. Hematother. Stem. Cell Res. 11, 863871. Chong, Z.Z., Kang, J.Q., Maiese, K., 2002b. Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106, 29732979. Chong, Z.Z., Kang, J.Q., Maiese, K., 2002c. Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J. Cereb. Blood Flow Metab. 22, 503514. Chong, Z.Z., Kang, J.Q., Maiese, K., 2003a. Apaf-1, Bcl-xL, cytochrome c, and caspase-9 form the critical elements for cerebral vascular protection by erythropoietin. J. Cereb. Blood Flow Metab. 23, 320330. Chong, Z.Z., Kang, J.Q., Maiese, K., 2003b. Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br. J. Pharmacol. 138, 11071118. Chong, Z.Z., Kang, J.Q., Maiese, K., 2003c. Erythropoietin: cytoprotection in vascular and neuronal cells. Curr. Drug Targets Cardiovasc. Haematol. Disord. 3, 141154. Chong, Z.Z., Kang, J.Q., Maiese, K., 2003d. Metabotropic glutamate receptors promote neuronal and vascular plasticity through novel intracellular pathways. Histol. Histopathol. 18, 173189. Chong, Z.Z., Kang, J.Q., Maiese, K., 2004a. Akt1 drives endothelial cell membrane asymmetry and microglial activation through Bcl-x(L) and caspases 1, 3, and 9. Exp. Cell Res. 296, 196207. Chong, Z.Z., Kang, J.Q., Maiese, K., 2004b. Essential cellular regulatory elements of oxidative stress in early and late phases of apoptosis in the central nervous system. Antioxid. Redox Signal. 6, 277287. Chong, Z.Z., Li, F., Maiese, K., 2005a. Activating Akt and the brains resources to drive cellular survival and prevent inammatory injury. Histol. Histopathol. 20, 299315. Chong, Z.Z., Li, F., Maiese, K., 2005b. Employing new cellular therapeutic targets for Alzheimers disease: a change for the better? Curr. Neurovasc. Res. 2, 5572. Chong, Z.Z., Lin, S.H., Maiese, K., 2004c. The NAD+ precursor nicotinamide governs neuronal survival during oxidative stress through protein kinase B coupled to FOXO3a and mitochondrial membrane potential. J. Cereb. Blood Flow Metab. 24, 728743. Chong, Z.Z., Lin, S.H., Maiese, K., 2002d. Nicotinamide modulates mitochondrial membrane potential and cysteine protease activity during cerebral vascular endothelial cell injury. J. Vasc. Res. 39, 131147. Chong, Z.Z., Lin, S.H., Kang, J.Q., Maiese, K., 2003e. Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspases 1, 3, and 8. J. Neurosci. Res. 71, 659669. Chong, Z.Z., Lin, S.H., Kang, J.Q., Maiese, K., 2003f. The tyrosine phosphatase SHP2 modulates MAP kinase p38 and caspases 1 and 3 to foster neuronal survival. Cell Mol. Neurobiol. 23, 561578. Chua, B.T., Guo, K., Li, P., 2000. Direct cleavage by the calcium-activated protease calpain can lead to inactivation of caspases. J. Biol. Chem. 275, 51315135. Citron, M., Vigo-Pelfrey, C., Teplow, D.B., Miller, C., Schenk, D., Johnston, J., Winblad, B., Venizelos, N., Lannfelt, L., Selkoe, D.J., 1994. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc. Natl. Acad. Sci. U.S.A. 91, 1199311997. Clausen, F., Lundqvist, H., Ekmark, S., Lewen, A., Ebendal, T., Hillered, L., 2004. Oxygen free radical-dependent activation of extracellular signalregulated kinase mediates apoptosis-like cell death after traumatic brain injury. J. Neurotrauma 21, 11681182. Cleeter, M.W., Cooper, J.M., Schapira, A.H., 1992. Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium: evidence for free radical involvement. J. Neurochem. 58, 786789.
235
Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S., Smith Jr., K.R., Muizelaar, J.P., Wagner Jr., F.C., Marion, D.W., Luerssen, T.G., Chesnut, R.M., Schwartz, M., 2001. Lack of effect of induction of hypothermia after acute brain injury. N. Engl. J. Med. 344, 556 563. Colurso, G.J., Nilson, J.E., Vervoort, L.G., 2003. Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimers disease. Life Sci. 73, 17951803. Combs, C.K., Karlo, J.C., Kao, S.C., Landreth, G.E., 2001. Beta-amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 11791188. Conery, A.R., Cao, Y., Thompson, E.A., Townsend Jr., C.M., Ko, T.C., Luo, K., 2004. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nat. Cell Biol. 6, 366372. Cook, D.G., Sung, J.C., Golde, T.E., Felsenstein, K.M., Wojczyk, B.S., Tanzi, R.E., Trojanowski, J.Q., Lee, V.M., Doms, R.W., 1996. Expression and analysis of presenilin 1 in a human neuronal system: localization in cell bodies and dendrites. Proc. Natl. Acad. Sci. U.S.A. 93, 9223 9228. Cosulich, S.C., Worrall, V., Hedge, P.J., Green, S., Clarke, P.R., 1997. Regulation of apoptosis by BH3 domains in a cell-free system. Curr. Biol. 7, 913920. Crossthwaite, A.J., Hasan, S., Williams, R.J., 2002. Hydrogen peroxidemediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca2+ and PI3-kinase. J. Neurochem. 80, 24 35. Crowder, R.J., Freeman, R.S., 1998. Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufcient for the survival of nerve growth factor-dependent sympathetic neurons. J. Neurosci. 18, 2933 2943. Crowder, R.J., Freeman, R.S., 2000. Glycogen synthase kinase-3 beta activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal. J. Biol. Chem. 275, 3426634271. Damian, M.S., Ellenberg, D., Gildemeister, R., Lauermann, J., Simonis, G., Sauter, W., Georgi, C., 2004. Coenzyme Q10 combined with mild hypothermia after cardiac arrest: a preliminary study. Circulation 110, 30113016. Datta, S.R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., Greenberg, M.E., 1997. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231241. de la Monte, S.M., Chiche, J., von dem Bussche, A., Sanyal, S., Lahousse, S.A., Janssens, S.P., Bloch, K.D., 2003. Nitric oxide synthase-3 overexpression causes apoptosis and impairs neuronal mitochondrial function: relevance to Alzheimers-type neurodegeneration. Lab Invest. 83, 287298. de la Monte, S.M., Lu, B.X., Sohn, Y.K., Etienne, D., Kraft, J., Ganju, N., Wands, J.R., 2000. Aberrant expression of nitric oxide synthase III in Alzheimers disease: relevance to cerebral vasculopathy and neurodegeneration. Neurobiol. Aging 21, 309319. De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D.U., Jin, R., Jones, J., Cong, R., Franzoso, G., 2001. Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414, 308313. Deibel, M.A., Ehmann, W.D., Markesbery, W.R., 1996. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimers disease: possible relation to oxidative stress. J. Neurol. Sci. 143, 137 142. DeKosky, S.T., Abrahamson, E.E., Taffe, K.M., Dixon, C.E., Kochanek, P.M., Ikonomovic, M.D., 2004. Effects of post-injury hypothermia and nerve growth factor infusion on antioxidant enzyme activity in the rat: implications for clinical therapies. J. Neurochem. 90, 9981004. Demougeot, C., Van Hoecke, M., Bertrand, N., Prigent-Tessier, A., Mossiat, C., Beley, A., Marie, C., 2004. Cytoprotective efcacy and mechanisms of the liposoluble iron chelator 2,20 -dipyridyl in the rat photothrombotic ischemic stroke model. J. Pharmacol. Exp. Ther.
236
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Fernando, R.I., Wimalasena, J., 2004. Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. Mol. Biol. Cell 15, 32663284. Ferrari, G., Yan, C.Y., Greene, L.A., 1995. N-Acetylcysteine (D- and Lstereoisomers) prevents apoptotic death of neuronal cells. J. Neurosci. 15, 28572866. Flaherty, D.B., Soria, J.P., Tomasiewicz, H.G., Wood, J.G., 2000. Phosphorylation of human tau protein by microtubule-associated kinases: GSK3beta and cdk5 are key participants. J. Neurosci. Res. 62, 463472. Floyd, R.A., Carney, J.M., 1992. Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann. Neurol. 32, S22S27. Fontaine, V., Mohand-Said, S., Hanoteau, N., Fuchs, C., Pzenmaier, K., Eisel, U., 2002. Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 22, RC216. Francois, F., Godinho, M.J., Grimes, M.L., 2000. CREB is cleaved by caspases during neural cell apoptosis. FEBS Lett. 486, 281284. Frech, M., Andjelkovic, M., Ingley, E., Reddy, K.K., Falck, J.R., Hemmings, B.A., 1997. High afnity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their inuence on kinase activity. J. Biol. Chem. 272, 84748481. Friguls, B., Justicia, C., Pallas, M., Planas, A.M., 2001. Focal cerebral ischemia causes two temporal waves of Akt activation. Neuroreport 12, 33813384. Frye, R.A., 2000. Phylogenetic classication of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793798. Fubini, B., Hubbard, A., 2003. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inammation and brosis. Free Radic. Biol. Med. 34, 15071516. Gallo, C.M., Smith Jr., D.L., Smith, J.S., 2004. Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity. Mol. Cell Biol. 24, 13011312. Gamblin, T.C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A.L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., Miller, R., Berry, R.W., Binder, L.I., Cryns, V.L., 2003. Caspase cleavage of tau: linking amyloid and neurobrillary tangles in Alzheimers disease. Proc. Natl. Acad. Sci. U.S.A. 100, 1003210037. Gao, G., Dou, Q.P., 2000. N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome c release and apoptotic cell death. J. Cell Biochem. 80, 53 72. Garrido, J.L., Godoy, J.A., Alvarez, A., Bronfman, M., Inestrosa, N.C., 2002. Protein kinase C inhibits amyloid beta peptide neurotoxicity by acting on members of the Wnt pathway. Faseb. J. 16, 19821984. Gastard, M.C., Troncoso, J.C., Koliatsos, V.E., 2003. Caspase activation in the limbic cortex of subjects with early Alzheimers disease. Ann. Neurol. 54, 393398. Genc, S., Koroglu, T.F., Genc, K., 2004. Erythropoietin as a novel neuroprotectant. Res. Neurol. Neurosci. 22, 105119. Gilley, J., Coffer, P.J., Ham, J., 2003. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J. Cell Biol. 162, 613622. Giovanni, A., Wirtz-Brugger, F., Keramaris, E., Slack, R., Park, D.S., 1999. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F DP, in B-amyloid-induced neuronal death. J. Biol. Chem. 274, 1901119016. Goldshmit, Y., Erlich, S., Pinkas-Kramarski, R., 2001. Neuregulin rescues PC12-ErbB4 cells from cell death induced by H(2)O(2). Regulation of reactive oxygen species levels by phosphatidylinositol 3-kinase. J. Biol. Chem. 276, 4637946385. Gottlieb, E., Vander Heiden, M.G., Thompson, C.B., 2000. Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol. Cell Biol. 20, 56805689.
Dewar, D., Chalmers, D.T., Graham, D.I., McCulloch, J., 1991. Glutamate metabotropic and AMPA binding sites are reduced in Alzheimers disease: an autoradiographic study of the hippocampus. Brain Res. 553, 5864. Di Lisa, F., Menabo, R., Canton, M., Barile, M., Bernardi, P., 2001. Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytes in postischemic reperfusion of the heart. J. Biol. Chem. 276, 25712575. Dijkers, P.F., Birkenkamp, K.U., Lam, E.W., Thomas, N.S., Lammers, J.W., Koenderman, L., Coffer, P.J., 2002. FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase Benhanced cell survival through maintenance of mitochondrial integrity. J. Cell Biol. 156, 531542. Dijkers, P.F., Medema, R.H., Pals, C., Banerji, L., Thomas, N.S., Lam, E.W., Burgering, B.M., Raaijmakers, J.A., Lammers, J.W., Koenderman, L., Coffer, P.J., 2000. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell Biol. 20, 91389148. Dombroski, D., Balasubramanian, K., Schroit, A.J., 2000. Phosphatidylserine expression on cell surfaces promotes antibody-dependent aggregation and thrombosis in beta2-glycoprotein I-immune mice. J. Autoimmun. 14, 221229. Doonan, F., Cotter, T., 2004. Apoptosis: a potential therapeutic target for retinal degenerations. Curr. Neurovasc. Res. 1, 4153. Dramsi, S., Scheid, M.P., Maiti, A., Hojabrpour, P., Chen, X., Schubert, K., Goodlett, D.R., Aebersold, R., Duronio, V., 2002. Identication of a novel phosphorylation site, Ser-170, as a regulator of bad pro-apoptotic activity. J. Biol. Chem. 277, 63996405. Du, L., Zhang, X., Han, Y.Y., Burke, N.A., Kochanek, P.M., Watkins, S.C., Graham, S.H., Carcillo, J.A., Szabo, C., Clark, R.S., 2003. Intramitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. J. Biol. Chem. 278, 18426 18433. Dzietko, M., Felderhoff-Mueser, U., Sifringer, M., Krutz, B., Bittigau, P., Thor, F., Heumann, R., Buhrer, C., Ikonomidou, C., Hansen, H.H., 2004. Erythropoietin protects the developing brain against N-methyl-Daspartate receptor antagonist neurotoxicity. Neurobiol. Dis. 15, 177 187. Earnshaw, W.C., Martins, L.M., Kaufmann, S.H., 1999. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu. Rev. Biochem. 68, 383424. El-Khodor, B.F., Oo, T.F., Kholodilov, N., Burke, R.E., 2003. Ectopic expression of cell cycle markers in models of induced programmed cell death in dopamine neurons of the rat substantia nigra pars compacta. Exp. Neurol. 179, 1727. Eliasson, M.J., Huang, Z., Ferrante, R.J., Sasamata, M., Molliver, M.E., Snyder, S.H., Moskowitz, M.A., 1999. Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. J. Neurosci. 19, 59105918. Elron, M., Soustiel, J.F., Guilburd, J.N., Zaaroor, M., Feinsod, M., 1998. Profuse hemorrhage from cerebral vessels in tangential missile injuries. Acta Neurochir. (Wien) 140, 255259. Engels, I.H., Stepczynska, A., Stroh, C., Lauber, K., Berg, C., Schwenzer, R., Wajant, H., Janicke, R.U., Porter, A.G., Belka, C., Gregor, M., Schulze-Osthoff, K., Wesselborg, S., 2000. Caspase-8/FLICE functions as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 19, 45634573. Fadok, V.A., de Cathelineau, A., Daleke, D.L., Henson, P.M., Bratton, D.L., 2001. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and broblasts. J. Biol. Chem. 276, 10711077. Farias, G.G., Godoy, J.A., Vazquez, M.C., Adani, R., Meshulam, H., Avila, J., Amitai, G., Inestrosa, N.C., 2005. The anti-inammatory and cholinesterase inhibitor bifunctional compound IBU-PO protects from betaamyloid neurotoxicity by acting on Wnt signaling components. Neurobiol. Dis. 18, 176183.
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Green, E.J., Dietrich, W.D., van Dijk, F., Busto, R., Markgraf, C.G., McCabe, P.M., Ginsberg, M.D., Schneiderman, N., 1992. Protective effects of brain hypothermia on behavior and histopathology following global cerebral ischemia in rats. Brain Res. 580, 197204. Gregoli, P.A., Bondurant, M.C., 1997. The roles of Bcl-X(L) and apopain in the control of erythropoiesis by erythropoietin. Blood 90, 630640. Grifths, P.D., Dobson, B.R., Jones, G.R., Clarke, D.T., 1999. Iron in the basal ganglia in Parkinsons disease. An in vitro study using extended Xray absorption ne structure and cryo-electron microscopy. Brain 122, 667673. Grimm, C., Wenzel, A., Groszer, M., Mayser, H., Seeliger, M., Samardzija, M., Bauer, C., Gassmann, M., Reme, C.E., 2002. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat. Med. 8, 718724. Groc, L., Bezin, L., Foster, J.A., Jiang, H., Jackson, T.S., Weissmann, D., Levine, R.A., 2001. Lipid peroxidation-mediated oxidative stress and dopamine neuronal apoptosis in the substantia nigra during development. Neurochem. Int. 39, 127133. Gu, M., Gash, M.T., Mann, V.M., Javoy-Agid, F., Cooper, J.M., Schapira, A.H., 1996. Mitochondrial defect in Huntingtons disease caudate nucleus. Ann. Neurol. 39, 385389. Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S.F., Geddes, J.W., Bondada, V., Rangnekar, V.M., Mattson, M.P., 1998. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat. Med. 4, 957962. Gursoy-Ozdemir, Y., Can, A., Dalkara, T., 2004. Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35, 14491453. Hall, E.D., Detloff, M.R., Johnson, K., Kupina, N.C., 2004. Peroxynitritemediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury. J. Neurotrauma 21, 920. Hanayama, R., Tanaka, M., Miyasaka, K., Aozasa, K., Koike, M., Uchiyama, Y., Nagata, S., 2004. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-decient mice. Science 304, 1147 1150. Hashimoto, T., Yonetani, M., Nakamura, H., 2003a. Selective brain hypothermia protects against hypoxic-ischemic injury in newborn rats by reducing hydroxyl radical production. Kobe J. Med. Sci. 49, 8391. Hashimoto, Y., Niikura, T., Chiba, T., Tsukamoto, E., Kadowaki, H., Nishitoh, H., Yamagishi, Y., Ishizaka, M., Yamada, M., Nawa, M., Terashita, K., Aiso, S., Ichijo, H., Nishimoto, I., 2003b. The cytoplasmic domain of Alzheimers amyloid-beta protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinasemediated neurotoxic signal via dimerization. J. Pharmacol. Exp. Ther. 306, 889902. Hatori, K., Nagai, A., Heisel, R., Ryu, J.K., Kim, S.U., 2002. Fractalkine and fractalkine receptors in human neurons and glial cells. J. Neurosci. Res. 69, 418426. Hatsugai, N., Kuroyanagi, M., Yamada, K., Meshi, T., Tsuda, S., Kondo, M., Nishimura, M., Hara-Nishimura, I., 2004. A plant vacuolar protease, VPE, mediates virus-induced hypersensitive cell death. Science 305, 855858. Hayashi, T., Saito, A., Okuno, S., Ferrand-Drake, M., Dodd, R.L., Nishi, T., Maier, C.M., Kinouchi, H., Chan, P.H., 2003. Oxidative damage to the endoplasmic reticulum is implicated in ischemic neuronal cell death. J. Cereb. Blood Flow Metab. 23, 11171128. Henry, M.K., Lynch, J.T., Eapen, A.K., Quelle, F.W., 2001. DNA damageinduced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway. Blood 98, 834841. Herbert, V., Shaw, S., Jayatilleke, E., Stopler-Kasdan, T., 1994. Most freeradical injury is iron-related: it is promoted by iron, hemin, holoferritin and Vitamin C, and inhibited by desferoxamine and apoferritin. Stem Cells 12, 289303. Hoffmann, P.R., de Cathelineau, A.M., Ogden, C.A., Leverrier, Y., Bratton, D.L., Daleke, D.L., Ridley, A.J., Fadok, V.A., Henson, P.M., 2001. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Cell Biol. 155, 649659.
237
Hofmann, K., Bucher, P., Tschopp, J., 1997. The CARD domain: a new apoptotic signalling motif. Trends Biochem. Sci. 22, 155156. Hong, J.R., Lin, G.H., Lin, C.J., Wang, W.P., Lee, C.C., Lin, T.L., Wu, J.L., 2004. Phosphatidylserine receptor is required for the engulfment of dead apoptotic cells and for normal embryonic development in zebrash. Development 131, 54175427. Hong, M., Chen, D.C., Klein, P.S., Lee, V.M., 1997. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J. Biol. Chem. 272, 2532625332. Hong, S.C., Goto, Y., Lanzino, G., Soleau, S., Kassell, N.F., Lee, K.S., 1994. Neuroprotection with a calpain inhibitor in a model of focal cerebral ischemia. Stroke 25, 663669. Hongisto, V., Smeds, N., Brecht, S., Herdegen, T., Courtney, M.J., Coffey, E.T., 2003. Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol. Cell Biol. 23, 60276036. Hu, Y., Benedict, M.A., Ding, L., Nunez, G., 1999. Role of cytochrome c and dATP/ATP hydrolysis in Apaf-1-mediated caspase-9 activation and apoptosis. EMBO J. 18, 35863595. Huang, F.P., Zhou, L.F., Yang, G.Y., 1998. Effects of mild hypothermia on the release of regional glutamate and glycine during extended transient focal cerebral ischemia in rats. Neurochem. Res. 23, 991996. Huang, X., Atwood, C.S., Hartshorn, M.A., Multhaup, G., Goldstein, L.E., Scarpa, R.C., Cuajungco, M.P., Gray, D.N., Lim, J., Moir, R.D., Tanzi, R.E., Bush, A.I., 1999. The A beta peptide of Alzheimers disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry 38, 76097616. Huh, P.W., Belayev, L., Zhao, W., Koch, S., Busto, R., Ginsberg, M.D., 2000. Comparative neuroprotective efcacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia. J. Neurosurg. 92, 9199. Hypothermia after Cardiac Arrest Study Group, 2002. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 346, 549556. Ibayashi, S., Takano, K., Ooboshi, H., Kitazono, T., Sadoshima, S., Fujishima, M., 2000. Effect of selective brain hypothermia on regional cerebral blood ow and tissue metabolism using brain thermo-regulator in spontaneously hypertensive rats. Neurochem. Res. 25, 369375. Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S., Kikuchi, A., 1998. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3betadependent phosphorylation of beta-catenin. EMBO J. 17, 13711384. Imberti, R., Nieminen, A.L., Herman, B., Lemasters, J.J., 1993. Mitochondrial and glycolytic dysfunction in lethal injury to hepatocytes by tbutylhydroperoxide: protection by fructose, cyclosporin A and triuoperazine. J. Pharmacol. Exp. Ther. 265, 392400. Ino, H., Chiba, T., 2001. Cyclin-dependent kinase 4 and cyclin D1 are required for excitotoxin-induced neuronal cell death in vivo. J. Neurosci. 21, 60866094. Ishihara, I., Minami, Y., Nishizaki, T., Matsuoka, T., Yamamura, H., 2000. Activation of calpain precedes morphological alterations during hydrogen peroxide-induced apoptosis in neuronally differentiated mouse embryonal carcinoma P19 cell line. Neurosci. Lett. 279, 97100. Ishitani, T., Ninomiya-Tsuji, J., Matsumoto, K., 2003. Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/ beta-catenin signaling. Mol. Cell Biol. 23, 13791389. Ivins Zito, C., Kontaridis, M.I., Fornaro, M., Feng, G.S., Bennett, A.M., 2004. SHP-2 regulates the phosphatidylinositide 30 -kinase/Akt pathway and suppresses caspase 3-mediated apoptosis. J. Cell Physiol. 199, 227 236. Iwashita, A., Maemoto, T., Nakada, H., Shima, I., Matsuoka, N., Hisajima, H., 2003. A novel potent radical scavenger, 8-(4-uorophenyl)-2-((2E)3-phenyl-2-propenoyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (FR210575), prevents neuronal cell death in cultured primary neurons and attenuates brain injury after focal ischemia in rats. J. Pharmacol. Exp. Ther. 307, 961968.
238
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 transient cerebral ischemia in rats. Stroke 31, 19821989, discussion 1989. Keller, J.N., Lauderback, C.M., Buttereld, D.A., Kindy, M.S., Yu, J., Markesbery, W.R., 2000. Amyloid beta-peptide effects on synaptosomes from apolipoprotein E-decient mice. J. Neurochem. 74, 15791586. Kennedy, S.G., Kandel, E.S., Cross, T.K., Hay, N., 1999. Akt/protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol. Cell Biol. 19, 58005810. Kermer, P., Klocker, N., Labes, M., Bahr, M., 2000. Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 in vivo. J. Neurosci. 20, 28. Kikuchi, A., Takeda, A., Onodera, H., Kimpara, T., Hisanaga, K., Sato, N., Nunomura, A., Castellani, R.J., Perry, G., Smith, M.A., Itoyama, Y., 2002. Systemic increase of oxidative nucleic acid damage in Parkinsons disease and multiple system atrophy. Neurobiol. Dis. 9, 244248. Kim, H.S., Lee, J.H., Lee, J.P., Kim, E.M., Chang, K.A., Park, C.H., Jeong, S.J., Wittendorp, M.C., Seo, J.H., Choi, S.H., Suh, Y.H., 2002. Amyloid beta peptide induces cytochrome c release from isolated mitochondria. Neuroreport 13, 19891993. Kirkland, R.A., Windelborn, J.A., Kasprzak, J.M., Franklin, J.L., 2002. A Bax-induced pro-oxidant state is critical for cytochrome c release during programmed neuronal death. J. Neurosci. 22, 64806490. Kirschenbaum, F., Hsu, S.C., Cordell, B., McCarthy, J.V., 2001. Glycogen synthase kinase-3beta regulates presenilin 1 C-terminal fragment levels. J. Biol. Chem. 276, 3070130707. Kish, S.J., Mastrogiacomo, F., Guttman, M., Furukawa, Y., Taanman, J.W., Dozic, S., Pandolfo, M., Lamarche, J., DiStefano, L., Chang, L.J., 1999. Decreased brain protein levels of cytochrome oxidase subunits in Alzheimers disease and in hereditary spinocerebellar ataxia disorders: a nonspecic change? J. Neurochem. 72, 700707. Kitagawa, K., Matsumoto, M., Tagaya, M., Hata, R., Ueda, H., Niinobe, M., Handa, N., Fukunaga, R., Kimura, K., Mikoshiba, K., et al., 1990. Ischemic tolerance phenomenon found in the brain. Brain Res. 528, 2124. Klotz, L.O., Schieke, S.M., Sies, H., Holbrook, N.J., 2000. Peroxynitrite activates the phosphoinositide 3-kinase/Akt pathway in human skin primary broblasts. Biochem. J. 352 (Pt 1), 219225. Koh, S.H., Kim, S.H., Kwon, H., Park, Y., Kim, K.S., Song, C.W., Kim, J., Kim, M.H., Yu, H.J., Henkel, J.S., Jung, H.K., 2003. Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. Brain Res. Mol. Brain Res. 118, 7281. Konishi, Y., Bonni, A., 2003. The E2F-Cdc2 cell-cycle pathway specically mediates activity deprivation-induced apoptosis of postmitotic neurons. J. Neurosci. 23, 16491658. Kops, G.J., Dansen, T.B., Polderman, P.E., Saarloos, I., Wirtz, K.W., Coffer, P.J., Huang, T.T., Bos, J.L., Medema, R.H., Burgering, B.M., 2002. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316321. Koriyama, Y., Chiba, K., Mohri, T., 2003. Propentofylline protects betaamyloid protein-induced apoptosis in cultured rat hippocampal neurons. Eur. J. Pharmacol. 458, 235241. Kovacs, D.M., Fausett, H.J., Page, K.J., Kim, T.W., Moir, R.D., Merriam, D.E., Hollister, R.D., Hallmark, O.G., Mancini, R., Felsenstein, K.M., Hyman, B.T., Tanzi, R.E., Wasco, W., 1996. Alzheimerassociated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells. Nat. Med. 2, 224229. Kowaltowski, A.J., Vercesi, A.E., Fiskum, G., 2000. Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides. Cell Death Differ. 7, 903910. Kremer, J.J., Sklansky, D.J., Murphy, R.M., 2001. Prole of changes in lipid bilayer structure caused by beta-amyloid peptide. Biochemistry 40, 85638571.
Jackson, M.D., Schmidt, M.T., Oppenheimer, N.J., Denu, J.M., 2003. Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J. Biol. Chem. 278, 5098550998. Jessel, R., Haertel, S., Socaciu, C., Tykhonova, S., Diehl, H.A., 2002. Kinetics of apoptotic markers in exogeneously induced apoptosis of EL4 cells. J. Cell Mol. Med. 6, 8292. Jolly-Tornetta, C., Gao, Z.Y., Lee, V.M., Wolf, B.A., 1998. Regulation of amyloid precursor protein secretion by glutamate receptors in human Ntera 2 neurons. J. Biol. Chem. 273, 1401514021. Jonassen, A.K., Sack, M.N., Mjos, O.D., Yellon, D.M., 2001. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ. Res. 89, 11911198. Jones, S.E., Jomary, C., Grist, J., Stewart, H.J., Neal, M.J., 2000. Modulated expression of secreted frizzled-related proteins in human retinal degeneration. Neuroreport 11, 39633967. Jope, R.S., Johnson, G.V., 2004. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95102. Jordan, J., Galindo, M.F., Miller, R.J., 1997. Role of calpain- and interleukin-1 beta converting enzyme-like proteases in the beta-amyloidinduced death of rat hippocampal neurons in culture. J. Neurochem. 68, 16121621. Jung, C., Rong, Y., Doctrow, S., Baudry, M., Malfroy, B., Xu, Z., 2001. Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model. Neurosci. Lett. 304, 157160. Juo, P., Kuo, C.J., Yuan, J., Blenis, J., 1998. Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade. Curr. Biol. 8, 10011008. Kalwy, S.A., Akbar, M.T., Cofn, R.S., de Belleroche, J., Latchman, D.S., 2003. Heat shock protein 27 delivered via a herpes simplex virus vector can protect neurons of the hippocampus against kainic-acid-induced cell loss. Brain Res. Mol. Brain Res. 111, 91103. Kameya, S., Hawes, N.L., Chang, B., Heckenlively, J.R., Naggert, J.K., Nishina, P.M., 2002. Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. Human Mol. Genet. 11, 18791886. Kamp, A., Posmantur, R., Nixon, R., Grynspan, F., Zhao, X., Liu, S.J., Newcomb, J.K., Clifton, G.L., Hayes, R.L., 1996. Mu-calpain activation and calpain-mediated cytoskeletal proteolysis following traumatic brain injury. J. Neurochem. 67, 15751583. Kang, J.Q., Chong, Z.Z., Maiese, K., 2003a. Akt1 protects against inammatory microglial activation through maintenance of membrane asymmetry and modulation of cysteine protease activity. J. Neurosci. Res. 74, 3751. Kang, J.Q., Chong, Z.Z., Maiese, K., 2003b. Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation. Mol. Pharmacol. 64, 557569. Kaptanoglu, E., Solaroglu, I., Okutan, O., Surucu, H.S., Akbiyik, F., Beskonakli, E., 2004. Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural ndings. Neurosurg. Rev. 27, 113120. Karibe, H., Zarow, G.J., Graham, S.H., Weinstein, P.R., 1994. Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, bloodbrain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 14, 620627. Kashour, T., Burton, T., Dibrov, A., Amara, F.M., 2003. Late simian virus 40 transcription factor is a target of the phosphoinositide 3-kinase/Akt pathway in anti-apoptotic Alzheimers amyloid precursor protein signalling. Biochem. J. 370, 10631075. Katner, A.L., Hoang, Q.B., Gootam, P., Jaruga, E., Ma, Q., Gnarra, J., Rayford, W., 2002. Induction of cell cycle arrest and apoptosis in human prostate carcinoma cells by a recombinant adenovirus expressing p27(Kip1). Prostate 53, 7787. Kawai, N., Okauchi, M., Morisaki, K., Nagao, S., 2000. Effects of delayed intraischemic and postischemic hypothermia on a focal model of
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Kronke, G., Bochkov, V.N., Huber, J., Gruber, F., Bluml, S., Furnkranz, A., Kadl, A., Binder, B.R., Leitinger, N., 2003. Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. J. Biol. Chem. 278, 51006 51014. Kuhl, M., Sheldahl, L.C., Park, M., Miller, J.R., Moon, R.T., 2000. The Wnt/ Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape. Trends Genet. 16, 279283. Kumral, A., Uysal, N., Tugyan, K., Sonmez, A., Yilmaz, O., Gokmen, N., Kiray, M., Genc, S., Duman, N., Koroglu, T.F., Ozkan, H., Genc, K., 2004. Erythropoietin improves long-term spatial memory decits and brain injury following neonatal hypoxia-ischemia in rats. Behav. Brain Res. 153, 7786. Kuwako, K., Nishimura, I., Uetsuki, T., Saido, T.C., Yoshikawa, K., 2002. Activation of calpain in cultured neurons overexpressing Alzheimer amyloid precursor protein. Brain Res. Mol. Brain Res. 107, 166175. Kwon, J.Y., Bacher, A., Deyo, D.J., Grafe, M.R., Disterhoft, J.F., Uchida, T., Zornow, M.H., 1999. Effects of hypothermia and lamotrigine on traceconditioned learning after global cerebral ischemia in rabbits. Exp. Neurol. 159, 105113. Lah, J.J., Heilman, C.J., Nash, N.R., Rees, H.D., Yi, H., Counts, S.E., Levey, A.I., 1997. Light and electron microscopic localization of presenilin-1 in primate brain. J. Neurosci. 17, 19711980. Laine, J., Kunstle, G., Obata, T., Sha, M., Noguchi, M., 2000. The protooncogene TCL1 is an Akt kinase coactivator. Mol. Cell 6, 395407. Latchman, D., 2004. Protective effect of heat shock proteins in the nervous system. Curr. Neurovasc. Res. 1, 2127. Lauber, K., Bohn, E., Krober, S.M., Xiao, Y.J., Blumenthal, S.G., Lindemann, R.K., Marini, P., Wiedig, C., Zobywalski, A., Baksh, S., Xu, Y., Autenrieth, I.B., Schulze-Osthoff, K., Belka, C., Stuhler, G., Wesselborg, S., 2003. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717 730. Law, A., Gauthier, S., Quirion, R., 2003. Alteration of nitric oxide synthase activity in young and aged apolipoprotein E-decient mice. Neurobiol. Aging 24, 187190. Lee, D.H., OConnor, T.R., Pfeifer, G.P., 2002. Oxidative DNA damage induced by copper and hydrogen peroxide promotes CG ! TT tandem mutations at methylated CpG dinucleotides in nucleotide excision repair-decient cells. Nucl. Acids Res. 30, 35663573. Lee, H.Y., Kleber, M., Hari, L., Brault, V., Suter, U., Taketo, M.M., Kemler, R., Sommer, L., 2004. Instructive role of Wnt/beta-catenin in sensory fate specication in neural crest stem cells. Science 303, 10201023. Lee, J.O., Yang, H., Georgescu, M.M., Di Cristofano, A., Maehama, T., Shi, Y., Dixon, J.E., Pandol, P., Pavletich, N.P., 1999. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell 99, 323334. Lee, R.K., Jimenez, J., Cox, A.J., Wurtman, R.J., 1996. Metabotropic glutamate receptors regulate APP processing in hippocampal neurons and cortical astrocytes derived from fetal rats. Ann. NY Acad. Sci. 777, 338343. Lee, Y.W., Park, H.J., Son, K.W., Hennig, B., Robertson, L.W., Toborek, M., 2003. 2,20 ,4,6,60 -Pentachlorobiphenyl (PCB 104) induces apoptosis of human microvascular endothelial cells through the caspase-dependent activation of CREB. Toxicol. Appl. Pharmacol. 189, 110. Lemeshko, S.V., Lemeshko, V.V., 2000. Metabolically derived potential on the outer membrane of mitochondria: a computational model. Biophys. J. 79, 27852800. Li, F., Chong, Z.Z., Maiese, K., 2004a. Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Neurosignals 13, 265289. Li, F., Chong, Z.Z., Maiese, K., 2004b. Navigating novel mechanisms of cellular plasticity with the NAD+ precursor and nutrient nicotinamide. Front. Biosci. 9, 25002520. Li, H., Zhu, H., Xu, C.J., Yuan, J., 1998. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491501.
239
Li, L.Y., Luo, X., Wang, X., 2001a. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412, 9599. Li, Y., Tennekoon, G.I., Birnbaum, M., Marchionni, M.A., Rutkowski, J.L., 2001b. Neuregulin signaling through a PI3K/Akt/Bad pathway in Schwann cell survival. Mol. Cell Neurosci. 17, 761767. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., Wang, X., 1997a. cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479489. Li, Y., Chopp, M., Powers, C., Jiang, N., 1997b. Apoptosis and protein expression after focal cerebral ischemia in rat. Brain Res. 765, 301312. Liebetrau, M., Staufer, B., Auerswald, E.A., Gabrijelcic-Geiger, D., Fritz, H., Zimmermann, C., Pfefferkorn, T., Hamann, G.F., 1999. Increased intracellular calpain detection in experimental focal cerebral ischemia. Neuroreport 10, 529534. Lin, S.J., Guarente, L., 2003. Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr. Opin. Cell Biol. 15, 241246. Lin, S.H., Maiese, K., 2001. The metabotropic glutamate receptor system protects against ischemic free radical programmed cell death in rat brain endothelial cells. J. Cereb. Blood Flow Metab. 21, 262275. Lin, H., Zhu, Y.J., Lal, R., 1999. Amyloid beta protein (140) forms calcium-permeable, Zn2+-sensitive channel in reconstituted lipid vesicles. Biochemistry 38, 1118911196. Lin, S.H., Chong, Z.Z., Maiese, K., 2001. Cell cycle induction in postmitotic neurons proceeds in concert with the initial phase of programmed cell death in rat. Neurosci. Lett. 310, 173177. Lin, S.H., Chong, Z.Z., Maiese, K., 2002. The metabotropic glutamate receptor system: G-protein mediated pathways that modulate neuronal and vascular cellular injury. Curr. Med. Chem. Central Nervous Syst. Agents 2, 1728. Lin, S.H., Vincent, A., Shaw, T., Maynard, K.I., Maiese, K., 2000. Prevention of nitric oxide-induced neuronal injury through the modulation of independent pathways of programmed cell death. J. Cereb. Blood Flow Metab. 20, 13801391. Liu, B., Hong, J.S., 2003. Role of microglia in inammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 17. Liu, D., Wen, J., Liu, J., Li, L., 1999a. The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. Faseb. J. 13, 23182328. Liu, S.T., Howlett, G., Barrow, C.J., 1999b. Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the A beta peptide of Alzheimers disease. Biochemistry 38, 93739378. Liu, W., Kato, M., Akhand, A.A., Hayakawa, A., Suzuki, H., Miyata, T., Kurokawa, K., Hotta, Y., Ishikawa, N., Nakashima, I., 2000. 4-Hydroxynonenal induces a cellular redox status-related activation of the caspase cascade for apoptotic cell death. J. Cell Sci. 113 (Pt 4), 635641. Liu, X., Kim, C.N., Yang, J., Jemmerson, R., Wang, X., 1996. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147157. Loberg, R.D., Vesely, E., Brosius III, F.C., 2002. Enhanced glycogen synthase kinase-3beta activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism. J. Biol. Chem. 277, 4166741673. Loetscher, H., Deuschle, U., Brockhaus, M., Reinhardt, D., Nelboeck, P., Mous, J., Grunberg, J., Haass, C., Jacobsen, H., 1997. Presenilins are processed by caspase-type proteases. J. Biol. Chem. 272, 20655 20659. Love, S., Barber, R., Wilcock, G.K., 1999. Increased poly(ADP-ribosylation) of nuclear proteins in Alzheimers disease. Brain 122 (Pt 2), 247 253. Lovell, M.A., Gabbita, S.P., Markesbery, W.R., 1999. Increased DNA oxidation and decreased levels of repair products in Alzheimers disease ventricular CSF. J. Neurochem. 72, 771776.
240
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Maiese, K., Lin, S., Chong, Z.Z., 2001. Elucidating neuronal and vascular injury through the cytoprotective agent nicotinamide. Curr. Med. Chem.Immunol. Endocrinol. Metab. Agents 1, 257267. Maiese, K., Swiriduk, M., TenBroeke, M., 1996. Cellular mechanisms of protection by metabotropic glutamate receptors during anoxia and nitric oxide toxicity. J. Neurochem. 66, 24192428. Maiese, K., Vincent, A., Lin, S.H., Shaw, T., 2000. Group I and Group III metabotropic glutamate receptor subtypes provide enhanced neuroprotection. J. Neurosci. Res. 62, 257272. Maira, S.M., Galetic, I., Brazil, D.P., Kaech, S., Ingley, E., Thelen, M., Hemmings, B.A., 2001. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294, 374380. Mancini, D.M., Katz, S.D., Lang, C.C., LaManca, J., Hudaihed, A., Androne, A.S., 2003. Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure. Circulation 107, 294299. Mark, R.J., Lovell, M.A., Markesbery, W.R., Uchida, K., Mattson, M.P., 1997. A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J. Neurochem. 68, 255264. Marklund, N., Lewander, T., Clausen, F., Hillered, L., 2001. Effects of the nitrone radical scavengers PBN and S-PBN on in vivo trapping of reactive oxygen species after traumatic brain injury in rats. J. Cereb. Blood Flow Metab. 21, 12591267. Martin, D., Salinas, M., Lopez-Valdaliso, R., Serrano, E., Recuero, M., Cuadrado, A., 2001. Effect of the Alzheimer amyloid fragment A beta (2535) on Akt/PKB kinase and survival of PC12 cells. J. Neurochem. 78, 10001008. Maruyama, K., Usami, M., Kametani, F., Tomita, T., Iwatsubo, T., Saido, T.C., Mori, H., Ishiura, S., 2000. Molecular interactions between presenilin and calpain: inhibition of m-calpain protease activity by presenilin-1, -2 and cleavage of presenilin-1 by m-, mu-calpain. Int. J. Mol. Med. 5, 269273. Masliah, E., Alford, M., DeTeresa, R., Mallory, M., Hansen, L., 1996. Decient glutamate transport is associated with neurodegeneration in Alzheimers disease. Ann. Neurol. 40, 759766. Matsumura, Y., Saeki, E., Otsu, K., Morita, T., Takeda, H., Kuzuya, T., Hori, M., Kusuoka, H., 2001. Intracellular calcium level required for calpain activation in a single myocardial cell. J. Mol. Cell Cardiol. 33, 1133 1142. Matsuzaki, H., Tamatani, M., Mitsuda, N., Namikawa, K., Kiyama, H., Miyake, S., Tohyama, M., 1999. Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J. Neurochem. 73, 20372046. Mattson, M.P., 2004. Pathways towards and away from Alzheimers disease. Nature 430, 631639. McCormick, W.C., Hardy, J., Kukull, W.A., Bowen, J.D., Teri, L., Zitzer, S., Larson, E.B., 2001. Healthcare utilization and costs in managed care patients with Alzheimers disease during the last few years of life. J. Am. Geriatr. Soc. 49, 11561160. McGrath, L.T., McGleenon, B.M., Brennan, S., McColl, D., Mc, I.S., Passmore, A.P., 2001. Increased oxidative stress in Alzheimers disease as assessed with 4-hydroxynonenal but not malondialdehyde. QJM 94, 485490. McLaurin, J., Chakrabartty, A., 1996. Membrane disruption by Alzheimer beta-amyloid peptides mediated through specic binding to either phospholipids or gangliosides: implications for neurotoxicity. J. Biol. Chem. 271, 2648226489. McPhie, D.L., Coopersmith, R., Hines-Peralta, A., Chen, Y., Ivins, K.J., Manly, S.P., Kozlowski, M.R., Neve, K.A., Neve, R.L., 2003. DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J. Neurosci. 23, 69146927. McShea, A., Harris, P.L., Webster, K.R., Wahl, A.F., Smith, M.A., 1997. Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimers disease. Am. J. Pathol. 150, 19331939.
Lu, D.C., Rabizadeh, S., Chandra, S., Shayya, R.F., Ellerby, L.M., Ye, X., Salvesen, G.S., Koo, E.H., Bredesen, D.E., 2000. A second cytotoxic proteolytic peptide derived from amyloid beta-protein precursor. Nat. Med. 6, 397404. Lu, T., Pan, Y., Kao, S.Y., Li, C., Kohane, I., Chan, J., Yankner, B.A., 2004. Gene regulation and DNA damage in the ageing human brain. Nature 429, 883891. Lu, Y., Yu, Q., Liu, J.H., Zhang, J., Wang, H., Koul, D., McMurray, J.S., Fang, X., Yung, W.K., Siminovitch, K.A., Mills, G.B., 2003. Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J. Biol. Chem. 278, 40057 40066. Lucas, J.J., Hernandez, F., Gomez-Ramos, P., Moran, M.A., Hen, R., Avila, J., 2001. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J. 20, 2739. Lue, L.F., Brachova, L., Walker, D.G., Rogers, J., 1996. Characterization of glial cultures from rapid autopsies of Alzheimers and control patients. Neurobiol. Aging 17, 421429. Luo, Z., Fujio, Y., Kureishi, Y., Rudic, R.D., Daumerie, G., Fulton, D., Sessa, W.C., Walsh, K., 2000. Acute modulation of endothelial Akt/ PKB activity alters nitric oxide-dependent vasomotor activity in vivo. J. Clin. Invest. 106, 493499. Maciel, E.N., Vercesi, A.E., Castilho, R.F., 2001. Oxidative stress in Ca2+induced membrane permeability transition in brain mitochondria. J. Neurochem. 79, 12371245. Madaio, M.P., Fabbi, M., Tiso, M., Daga, A., Puccetti, A., 1996. Spontaneously produced anti-DNA/DNase I autoantibodies modulate nuclear apoptosis in living cells. Eur. J. Immunol. 26, 30353041. Maehama, T., Dixon, J.E., 1998. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 1337513378. Maier, C.M., Sun, G.H., Cheng, D., Yenari, M.A., Chan, P.H., Steinberg, G.K., 2002. Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol. Dis. 11, 2842. Maiese, K., 2001. The dynamics of cellular injury: transformation into neuronal and vascular protection. Histol. Histopathol. 16, 633644. Maiese, K., 2002. Organic brain disease. In: Ramachandran, V.S. (Ed.), Encyclopedia of the Human Brain. 1st ed. Elsevier Science, pp. 509 527. Maiese, K., 2004. Sequelae of cardiac arrest. Medlink Neurol. Maiese, K., Boccone, L., 1995. Neuroprotection by peptide growth factors against anoxia and nitric oxide toxicity requires modulation of protein kinase C. J. Cereb. Blood Flow Metab. 15, 440449. Maiese, K., Chong, Z.Z., 2003. Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain. Trends Pharmacol. Sci. 24, 228 232. Maiese, K., Chong, Z.Z., 2004. Insights into oxidative stress and potential novel therapeutic targets for Alzheimer disease. Restor. Neurol. Neurosci. 22, 87104. Maiese, K., Vincent, A.M., 2000. Membrane asymmetry and DNA degradation: functionally distinct determinants of neuronal programmed cell death. J. Neurosci. Res. 59, 568580. Maiese, K., Boniece, I.R., Skurat, K., Wagner, J.A., 1993. Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. J. Neurosci. Res. 36, 7787. Maiese, K., Chong, Z.Z., Kang, J., 2003. Transformation into treatment: novel therapeutics that begin within the cell. In: Maiese, K. (Ed.), Neuronal and Vascular Plasticity: Elucidating Basic Cellular Mechanisms for Future Therapeutic Discovery. Kluwer Academic Publishers, Norwell, MA, pp. 126. Maiese, K., Li, F., Chong, Z.Z., 2004. Erythropoietin in the brain: can the promise to protect be fullled? Trends Pharmacol. Sci. 25, 577 583. Maiese, K., Li, F., Chong, Z.Z., 2005. New avenues of exploration for erythropoietin. JAMA 293, 9095.
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Medema, R.H., Kops, G.J., Bos, J.L., Burgering, B.M., 2000. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782787. Mehlhorn, G., Hollborn, M., Schliebs, R., 2000. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int. J. Develop. Neurosci. 18, 423431. Mendiondo, M.S., Kryscio, R.J., Schmitt, F.A., 2001. Models of progression in AD: predicting disability and costs. Neurology 57, 943944. Miller, A.C., Stewart, M., Brooks, K., Shi, L., Page, N., 2002. Depleted uranium-catalyzed oxidative DNA damage: absence of signicant alpha particle decay. J. Inorg. Biochem. 91, 246252. Minoshima, S., Giordani, B., Berent, S., Frey, K.A., Foster, N.L., Kuhl, D.E., 1997. Metabolic reduction in the posterior cingulate cortex in very early Alzheimers disease. Ann. Neurol. 42, 8594. Mirzabekov, T., Lin, M.C., Yuan, W.L., Marshall, P.J., Carman, M., Tomaselli, K., Lieberburg, I., Kagan, B.L., 1994. Channel formation in planar lipid bilayers by a neurotoxic fragment of the beta-amyloid peptide. Biochem. Biophys. Res. Commun. 202, 11421148. Miyaoka, T., Seno, H., Ishino, H., 1999. Increased expression of Wnt-1 in schizophrenic brains. Schizophr. Res. 38, 16. Moldoveanu, T., Hoseld, C.M., Lim, D., Elce, J.S., Jia, Z., Davies, P.L., 2002. A Ca2+ switch aligns the active site of calpain. Cell 108, 649 660. Monji, A., Utsumi, H., Ueda, T., Imoto, T., Yoshida, I., Hashioka, S., Tashiro, K., Tashiro, N., 2001. The relationship between the aggregational state of the amyloid-beta peptides and free radical generation by the peptides. J. Neurochem. 77, 14251432. Montague, J.W., Hughes Jr., F., Cidlowski, J.A., 1997. Native recombinant cyclophilins A, B, and C degrade DNA independently of peptidylprolyl cistrans-isomerase activity. Potential roles of cyclophilins in apoptosis. J. Biol. Chem. 272, 66776684. Montine, T.J., Markesbery, W.R., Zackert, W., Sanchez, S.C., Roberts II, L.J., Morrow, J.D., 1999. The magnitude of brain lipid peroxidation correlates with the extent of degeneration but not with density of neuritic plaques or neurobrillary tangles or with APOE genotype in Alzheimers disease patients. Am. J. Pathol. 155, 863868. Moon, C., Krawczyk, M., Ahn, D., Ahmet, I., Paik, D., Lakatta, E.G., Talan, M.I., 2003. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats. Proc. Natl. Acad. Sci. U.S.A. 100, 1161211617. Mrsic-Pelcic, J., Zupan, G., Maysinger, D., Pelcic, G., Vitezic, D., Simonic, A., 2002. The inuence of MK-801 on the hippocampal free arachidonic acid level and Na+, K+-ATPase activity in global cerebral ischemiaexposed rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 26, 1319 1326. Mudher, A., Chapman, S., Richardson, J., Asuni, A., Gibb, G., Pollard, C., Killick, R., Iqbal, T., Raymond, L., Varndell, I., Sheppard, P., Makoff, A., Gower, E., Soden, P.E., Lewis, P., Murphy, M., Golde, T.E., Rupniak, H.T., Anderton, B.H., Lovestone, S., 2001. Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogenactivated protein kinase and c-Jun terminal kinase. J. Neurosci. 21, 49874995. Mukherjee, P.K., Marcheselli, V.L., Serhan, C.N., Bazan, N.G., 2004. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. U.S.A. 101, 84918496. Munoz-Montano, J.R., Moreno, F.J., Avila, J., Diaz-Nido, J., 1997. Lithium inhibits Alzheimers disease-like tau protein phosphorylation in neurons. FEBS Lett. 411, 183188. Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B.A., Yuan, J., 2000. Caspase-12 mediates endoplasmic-reticulum-specic apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98103. Nakano, T., Ishimoto, Y., Kishino, J., Umeda, M., Inoue, K., Nagata, K., Ohashi, K., Mizuno, K., Arita, H., 1997. Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specic gene 6. J. Biol. Chem. 272, 2941129414.
241
Nakatani, K., Sakaue, H., Thompson, D.A., Weigel, R.J., Roth, R.A., 1999. Identication of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochem. Biophys. Res. Commun. 257, 906910. Namikawa, K., Honma, M., Abe, K., Takeda, M., Mansur, K., Obata, T., Miwa, A., Okado, H., Kiyama, H., 2000. Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J. Neurosci. 20, 28752886. Namura, S., Nagata, I., Takami, S., Masayasu, H., Kikuchi, H., 2001. Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 32, 19061911. Naruse, I., Hoshino, H., Dobashi, K., Minato, K., Saito, R., Mori, M., 2000. Over-expression of p27kip1 induces growth arrest and apoptosis mediated by changes of pRb expression in lung cancer cell lines. Int. J. Cancer 88, 377383. Nelson, W.J., Nusse, R., 2004. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303, 14831487. Nishimura, I., Uetsuki, T., Kuwako, K., Hara, T., Kawakami, T., Aimoto, S., Yoshikawa, K., 2002. Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein. Cell Death Differ. 9, 199208. Nusse, R., 1999. WNT targets: repression and activation. Trends Genet. 15, 13. Obal, I., Jakab, J.S., Siklos, L., Engelhardt, J.I., 2001. Recruitment of activated microglia cells in the spinal cord of mice by ALS IgG. Neuroreport 12, 24492452. Olsen, N.V., 2003. Central nervous system frontiers for the use of erythropoietin. Clin. Infect. Dis. 37 (Suppl. 4), S323S330. Onizuka, K., Kunimatsu, M., Ozaki, Y., Muramatsu, K., Sasaki, M., Nishino, H., 1995. Distribution of mu-calpain proenzyme in the brain and other neural tissues in the rat. Brain Res. 697, 179 186. Owada, Y., Utsunomiya, A., Yoshimoto, T., Kondo, H., 1997. Expression of mRNA for Akt, serinethreonine protein kinase, in the brain during development and its transient enhancement following axotomy of hypoglossal nerve. J. Mol. Neurosci. 9, 2733. Padmanabhan, J., Park, D.S., Greene, L.A., Shelanski, M.L., 1999. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J. Neurosci. 19, 87478756. Palmer, A.M., Burns, M.A., 1994. Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimers disease. Brain Res. 645, 338342. Pandey, S., Walker, P.R., Sikorska, M., 1997. Identication of a novel 97 kDa endonuclease capable of internucleosomal DNA cleavage. Biochemistry 36, 711720. Pap, M., Cooper, G.M., 2002. Role of translation initiation factor 2B in control of cell survival by the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3beta signaling pathway. Mol. Cell Biol. 22, 578 586. Papapetropoulos, A., Fulton, D., Mahboubi, K., Kalb, R.G., OConnor, D.S., Li, F., Altieri, D.C., Sessa, W.C., 2000. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J. Biol. Chem. 275, 91029105. Papkoff, J., Aikawa, M., 1998. WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. Biochem. Biophys. Res. Commun. 247, 851858. Paradis, E., Douillard, H., Koutroumanis, M., Goodyer, C., LeBlanc, A., 1996. Amyloid beta peptide of Alzheimers disease downregulates Bcl2 and upregulates bax expression in human neurons. J. Neurosci. 16, 75337539. Parsa, C.J., Kim, J., Riel, R.U., Pascal, L.S., Thompson, R.B., Petrofski, J.A., Matsumoto, A., Stamler, J.S., Koch, W.J., 2004. Cardioprotective effects of erythropoietin in the reperfused ischemic heart: a potential role for cardiac broblasts. J. Biol. Chem.. Parsa, C.J., Matsumoto, A., Kim, J., Riel, R.U., Pascal, L.S., Walton, G.B., Thompson, R.B., Petrofski, J.A., Annex, B.H., Stamler, J.S., Koch, W.J.,
242
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 intracellular levels of amyloid beta-protein 42 in Chinese hamster ovary cells. Biochemistry 42, 10421052. Raina, A.K., Zhu, X., Rottkamp, C.A., Monteiro, M., Takeda, A., Smith, M.A., 2000. Cyclin toward dementia: cell cycle abnormalities and abortive oncogenesis in Alzheimer disease. J. Neurosci. Res. 61, 128 133. Ray, S.K., Fidan, M., Nowak, M.W., Wilford, G.G., Hogan, E.L., Banik, N.L., 2000. Oxidative stress and Ca2+ inux upregulate calpain and induce apoptosis in PC12 cells. Brain Res. 852, 326334. Ray, S.K., Matzelle, D.D., Sribnick, E.A., Guyton, M.K., Wingrave, J.M., Banik, N.L., 2003. Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury. J. Chem. Neuroanat. 26, 119124. Reed, J.C., 2001. Apoptosis-regulating proteins as targets for drug discovery. Trends Mol. Med. 7, 314319. Reisberg, B., Doody, R., Stofer, A., Schmitt, F., Ferris, S., Mobius, H.J., 2003. Memantine in moderate-to-severe Alzheimers disease. N. Engl. J. Med. 348, 13331341. Religa, D., Winblad, B., 2003. Therapeutic strategies for Alzheimers disease based on new molecular mechanisms. Acta Neurobiol. Exp. (Wars.) 63, 393396. Ren, Y., Hashimoto, M., Pulsinelli, W.A., Nowak Jr., T.S., 2004. Hypothermic protection in rat focal ischemia models: strain differences and relevance to reperfusion injury. J. Cereb. Blood Flow Metab. 24, 42 53. Rena, G., Prescott, A.R., Guo, S., Cohen, P., Unterman, T.G., 2001. Roles of the Forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 1433 binding, transactivation and nuclear targeting. Biochem. J. 354, 605612. Rhee, C.S., Sen, M., Lu, D., Wu, C., Leoni, L., Rubin, J., Corr, M., Carson, D.A., 2002. Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 21, 65986605. Ribatti, D., Presta, M., Vacca, A., Ria, R., Giuliani, R., DellEra, P., Nico, B., Roncali, L., Dammacco, F., 1999. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood 93, 26272636. Rideout, H.J., Wang, Q., Park, D.S., Stefanis, L., 2003. Cyclin-dependent kinase activity is required for apoptotic death but not inclusion formation in cortical neurons after proteosomal inhibition. J. Neurosci. 23, 12371245. Riedel, G., Opitz, T., Reymann, K.G., 1996. Blockade of metabotropic glutamate receptors protects hippocampal neurons from hypoxiainduced cell death in rat in vivo. Prog. Neuropsychopharmacol. Biol. Psychiatry 20, 12531263. Rodrigues, C.M., Sola, S., Silva, R., Brites, D., 2000. Bilirubin and amyloidbeta peptide induce cytochrome c release through mitochondrial membrane permeabilization. Mol. Med. 6, 936946. Rogers, J., Lue, L.F., 2001. Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimers disease. Neurochem. Int. 39, 333340. Rohn, T.T., Head, E., Su, J.H., Anderson, A.J., Bahr, B.A., Cotman, C.W., Cribbs, D.H., 2001. Correlation between caspase activation and neurobrillary tangle formation in Alzheimers disease. Am. J. Pathol. 158, 189198. Rosen, D.R., Siddique, T., Patterson, D., Figlewicz, D.A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., ORegan, J.P., Deng, H.X., et al., 1993. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 5962. Rosso, S.B., Sussman, D., Wynshaw-Boris, A., Salinas, P.C., 2005. Wnt signaling through dishevelled, Rac and JNK regulates dendritic development. Nat. Neurosci. 8, 3442. Ruiz-Vela, A., Gonzalez de Buitrago, G., Martinez, A.C., 1999. Implication of calpain in caspase activation during B cell clonal deletion. EMBO J. 18, 49884998. Ruscher, K., Freyer, D., Karsch, M., Isaev, N., Megow, D., Sawitzki, B., Priller, J., Dirnagl, U., Meisel, A., 2002. Erythropoietin is a paracrine
2003. A novel protective effect of erythropoietin in the infarcted heart. J. Clin. Invest. 112, 9991007. Pasquet, J.M., Dachary-Prigent, J., Nurden, A.T., 1996. Calcium inux is a determining factor of calpain activation and microparticle formation in platelets. Eur. J. Biochem. 239, 647654. Patapoutian, A., Reichardt, L.F., 2000. Roles of Wnt proteins in neural development and maintenance. Curr. Opin. Neurobiol. 10, 392399. Patrick, G.N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., Tsai, L.H., 1999. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615622. Pei, J.J., Braak, E., Braak, H., Grundke-Iqbal, I., Iqbal, K., Winblad, B., Cowburn, R.F., 1999. Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurobrillary changes. J. Neuropathol. Exp. Neurol. 58, 10101019. Pei, J.J., Grundke-Iqbal, I., Iqbal, K., Bogdanovic, N., Winblad, B., Cowburn, R.F., 1998. Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimers disease neurobrillary degeneration. Brain Res. 797, 267277. Pekarsky, Y., Koval, A., Hallas, C., Bichi, R., Tresini, M., Malstrom, S., Russo, G., Tsichlis, P., Croce, C.M., 2000. Tcl1 enhances Akt kinase activity and mediates its nuclear translocation. Proc. Natl. Acad. Sci. U.S.A. 97, 30283033. Perez-Severiano, F., Santamaria, A., Pedraza-Chaverri, J., Medina-Campos, O.N., Rios, C., Segovia, J., 2004. Increased formation of reactive oxygen species, but no changes in glutathione peroxidase activity, in striata of mice transgenic for the Huntingtons disease mutation. Neurochem. Res. 29, 729733. Pfeiffer, S., Lass, A., Schmidt, K., Mayer, B., 2001. Protein tyrosine nitration in mouse peritoneal macrophages activated in vitro and in vivo: evidence against an essential role of peroxynitrite. Faseb. J. 15, 23552364. Philpott, K.L., McCarthy, M.J., Klippel, A., Rubin, L.L., 1997. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J. Cell Biol. 139, 809815. Plas, D.R., Talapatra, S., Edinger, A.L., Rathmell, J.C., Thompson, C.B., 2001. Akt and Bcl-xL promote growth factor-independent survival through distinct effects on mitochondrial physiology. J. Biol. Chem. 276, 1204112048. Pompl, P.N., Yemul, S., Xiang, Z., Ho, L., Haroutunian, V., Purohit, D., Mohs, R., Pasinetti, G.M., 2003. Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch. Neurol. 60, 369376. Posmantur, R., Kamp, A., Siman, R., Liu, J., Zhao, X., Clifton, G.L., Hayes, R.L., 1997. A calpain inhibitor attenuates cortical cytoskeletal protein loss after experimental traumatic brain injury in the rat. Neuroscience 77, 875888. Potter, D.A., Tirnauer, J.S., Janssen, R., Croall, D.E., Hughes, C.N., Fiacco, K.A., Mier, J.W., Maki, M., Herman, I.M., 1998. Calpain regulates actin remodeling during cell spreading. J. Cell Biol. 141, 647662. Przedborski, S., Kostic, V., Jackson-Lewis, V., Naini, A.B., Simonetti, S., Fahn, S., Carlson, E., Epstein, C.J., Cadet, J.L., 1992. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to Nmethyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 16581667. Pugazhenthi, S., Miller, E., Sable, C., Young, P., Heidenreich, K.A., Boxer, L.M., Reusch, J.E., 1999. Insulin-like growth factor-I induces bcl-2 promoter through the transcription factor cAMP-response elementbinding protein. J. Biol. Chem. 274, 2752927535. Pugazhenthi, S., Nesterova, A., Jambal, P., Audesirk, G., Kern, M., Cabell, L., Eves, E., Rosner, M.R., Boxer, L.M., Reusch, J.E., 2003. Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons. J. Neurochem. 84, 982996. Putcha, G.V., Deshmukh, M., Johnson Jr., E.M., 1999. BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J. Neurosci. 19, 74767485. Qi, Y., Morishima-Kawashima, M., Sato, T., Mitsumori, R., Ihara, Y., 2003. Distinct mechanisms by mutant presenilin 1 and 2 leading to increased
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 mediator of ischemic tolerance in the brain: evidence from an in vitro model. J. Neurosci. 22, 1029110301. Rytomaa, M., Lehmann, K., Downward, J., 2000. Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling. Oncogene 19, 44614468. Saeki, K., Yuo, A., Suzuki, E., Yazaki, Y., Takaku, F., 1999. Aberrant expression of cAMP-response-element-binding protein (CREB) induces apoptosis. Biochem. J. 343 (Pt 1), 249255. Sagara, Y., Schubert, D., 1998. The activation of metabotropic glutamate receptors protects nerve cells from oxidative stress. J. Neurosci. 18, 66626671. Sakamaki, K., 2004. Regulation of endothelial cell death and its role in angiogenesis and vascular regression. Curr. Neurovasc. Res. 1, 305315. Salas, T.R., Reddy, S.A., Clifford, J.L., Davis, R.J., Kikuchi, A., Lippman, S.M., Menter, D.G., 2003. Alleviating the suppression of glycogen synthase kinase-3beta by Akt leads to the phosphorylation of cAMPresponse element-binding protein and its transactivation in intact cell nuclei. J. Biol. Chem. 278, 4133841346. Salinas, M., Diaz, R., Abraham, N.G., Ruiz de Galarreta, C.M., Cuadrado, A., 2003. Nerve growth factor protects against 6-hydroxydopamineinduced oxidative stress by increasing expression of heme oxygenase-1 in a phosphatidylinositol 3-kinase-dependent manner. J. Biol. Chem. 278, 1389813904. Salinas, M., Martin, D., Alvarez, A., Cuadrado, A., 2001. Akt1/PKBalpha protects PC12 cells against the parkinsonism-inducing neurotoxin 1methyl-4-phenylpyridinium and reduces the levels of oxygen-free radicals. Mol. Cell Neurosci. 17, 6777. Sanderson, K.L., Butler, L., Ingram, V.M., 1997. Aggregates of a betaamyloid peptide are required to induce calcium currents in neuron-like human teratocarcinoma cells: relation to Alzheimers disease. Brain Res. 744, 714. Sankarapandi, S., Zweier, J.L., Mukherjee, G., Quinn, M.T., Huso, D.L., 1998. Measurement and characterization of superoxide generation in microglial cells: evidence for an NADPH oxidase-dependent pathway. Arch. Biochem. Biophys. 353, 312321. Sasaoka, T., Wada, T., Fukui, K., Murakami, S., Ishihara, H., Suzuki, R., Tobe, K., Kadowaki, T., Kobayashi, M., 2004. SH2-containing inositol phosphatase 2 predominantly regulates Akt2, and not Akt1, phosphorylation at the plasma membrane in response to insulin in 3T3-L1 adipocytes. J. Biol. Chem. 279, 1483514843. Sato, S., Fujita, N., Tsuruo, T., 2000. Modulation of Akt kinase activity by binding to Hsp90. Proc. Natl. Acad. Sci. U.S.A. 97, 1083210837. Satoh, M.S., Lindahl, T., 1992. Role of poly(ADP-ribose) formation in DNA repair. Nature 356, 356358. Savage, M.J., Trusko, S.P., Howland, D.S., Pinsker, L.R., Mistretta, S., Reaume, A.G., Greenberg, B.D., Siman, R., Scott, R.W., 1998. Turnover of amyloid beta-protein in mouse brain and acute reduction of its level by phorbol ester. J. Neurosci. 18, 17431752. Schmidt, M., Fernandez de Mattos, S., van der Horst, A., Klompmaker, R., Kops, G.J., Lam, E.W., Burgering, B.M., Medema, R.H., 2002. Cell cycle inhibition by FoxO Forkhead transcription factors involves downregulation of cyclin D. Mol. Cell Biol. 22, 78427852. Sharma, S.K., Ebadi, M., 2003. Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons. Antioxid. Redox Signal. 5, 251264. Shaw, M., Cohen, P., Alessi, D.R., 1997. Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKBinduced phosphorylation of Ser-9 and not by dephosphorylation of Tyr216. FEBS Lett. 416, 307311. Shea, T.B., 1997. Restriction of microM-calcium-requiring calpain activation to the plasma membrane in human neuroblastoma cells: evidence for regionalized inuence of a calpain activator protein. J. Neurosci. Res. 48, 543550. Sheng, J.G., Mrak, R.E., Grifn, W.S., 1997. Neuritic plaque evolution in Alzheimers disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms. Acta Neuropathol. (Berl.) 94, 15.
243
Shi, Y., 2004. Caspase activation: revisiting the induced proximity model. Cell 117, 855858. Shimura, M., Osawa, Y., Yuo, A., Hatake, K., Takaku, F., Ishizaka, Y., 2000. Oxidative stress as a necessary factor in room temperature-induced apoptosis of HL-60 cells. J. Leukoc. Biol. 68, 8796. Shin, S.Y., Kim, C.G., Jho, E.H., Rho, M.S., Kim, Y.S., Kim, Y.H., Lee, Y.H., 2004. Hydrogen peroxide negatively modulates Wnt signaling through downregulation of beta-catenin. Cancer Lett. 212, 225231. Shiraha, H., Glading, A., Gupta, K., Wells, A., 1999. IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J. Cell Biol. 146, 243254. Shirvan, A., Ziv, I., Zilkha-Falb, R., Machlyn, T., Barzilai, A., Melamed, E., 1998. Expression of cell cycle-related genes during neuronal apoptosis: is there a distinct pattern? Neurochem. Res. 23, 767777. Sik Eum, W., Won Kim, D., Koo Hwang, I., Yoo, K.Y., Kang, T.C., Ho Jang, S., Soon Choi, H., Hyun Choi, S., Hoon Kim, Y., Young Kim, S., Yil Kwon, H., Hoon Kang, J., Kwon, O.S., Cho, S.W., Soo Lee, K., Park, J., Ho Won, M., Young Choi, S., 2004. In vivo protein transduction: biologically active intact pep-1-superoxide dismutase fusion protein efciently protects against ischemic insult. Free Radic. Biol. Med. 37, 16561669. Silva, M., Grillot, D., Benito, A., Richard, C., Nunez, G., Fernandez-Luna, J.L., 1996. Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 88, 15761582. Silverberg, D.S., Wexler, D., Blum, M., Tchebiner, J.Z., Sheps, D., Keren, G., Schwartz, D., Baruch, R., Yachnin, T., Shaked, M., Schwartz, I., Steinbruch, S., Iaina, A., 2003. The effect of correction of anaemia in diabetics and non-diabetics with severe resistant congestive heart failure and chronic renal failure by subcutaneous erythropoietin and intravenous iron. Nephrol. Dial. Transplant. 18, 141146. Simak, J., Holada, K., Vostal, J.G., 2002. Release of annexin V-binding membrane microparticles from cultured human umbilical vein endothelial cells after treatment with camptothecin. BMC Cell Biol. 3, 11. Simakajornboon, N., Szerlip, N.J., Gozal, E., Anonetapipat, J.W., Gozal, D., 2001. In vivo PDGF beta receptor activation in the dorsocaudal brainstem of the rat prevents hypoxia-induced apoptosis via activation of Akt and BAD. Brain Res. 895, 111118. Singhrao, S.K., Neal, J.W., Morgan, B.P., Gasque, P., 1999. Increased complement biosynthesis by microglia and complement activation on neurons in Huntingtons disease. Exp. Neurol. 159, 362376. Siu, A.W., To, C.H., 2002. Nitric oxide and hydroxyl radical-induced retinal lipid peroxidation in vitro. Clin. Exp. Optom. 85, 378382. Skurk, C., Maatz, H., Kim, H.S., Yang, J., Abid, M.R., Aird, W.C., Walsh, K., 2004. The Akt-regulated Forkhead transcription factor FOXO3a controls endothelial cell viability through modulation of the caspase-8 inhibitor FLIP. J. Biol. Chem. 279, 15131525. Smeitink, J., van den Heuvel, L., Koopman, W., Nijtmans, L., Ugalde, C., Willems, P., 2004. Cell biological consequences of mitochondrial NADH: ubiquinone oxidoreductase deciency. Curr. Neurovasc. Res. 1, 2940. Smith, M.A., Hirai, K., Hsiao, K., Pappolla, M.A., Harris, P.L., Siedlak, S.L., Tabaton, M., Perry, G., 1998. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J. Neurochem. 70, 22122215. Soane, L., Cho, H.J., Niculescu, F., Rus, H., Shin, M.L., 2001. C5b-9 terminal complement complex protects oligodendrocytes from death by regulating Bad through phosphatidylinositol 3-kinase/Akt pathway. J. Immunol. 167, 23052311. Somervaille, T.C., Linch, D.C., Khwaja, A., 2001. Growth factor withdrawal from primary human erythroid progenitors induces apoptosis through a pathway involving glycogen synthase kinase-3 and Bax. Blood 98, 13741381. Sonoda, Y., Watanabe, S., Matsumoto, Y., Aizu-Yokota, E., Kasahara, T., 1999. FAK is the upstream signal protein of the phosphatidylinositol 3kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. J. Biol. Chem. 274, 1056610570.
244
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Tanaka, M., Sotomatsu, A., Yoshida, T., Hirai, S., Nishida, A., 1994. Detection of superoxide production by activated microglia using a sensitive and specic chemiluminescence assay and microglia-mediated PC12h cell death. J. Neurochem. 63, 266270. Tang, E.D., Nunez, G., Barr, F.G., Guan, K.L., 1999. Negative regulation of the Forkhead transcription factor FKHR by Akt. J. Biol. Chem. 274, 1674116746. Tang, G., Minemoto, Y., Dibling, B., Purcell, N.H., Li, Z., Karin, M., Lin, A., 2001. Inhibition of JNK activation through NF-kappaB target genes. Nature 414, 313317. Tang, K., Yang, J., Gao, X., Wang, C., Liu, L., Kitani, H., Atsumi, T., Jing, N., 2002. Wnt-1 promotes neuronal differentiation and inhibits gliogenesis in P19 cells. Biochem. Biophys. Res. Commun. 293, 167 173. Taniguchi, S., Fujita, Y., Hayashi, S., Kakita, A., Takahashi, H., Murayama, S., Saido, T.C., Hisanaga, S., Iwatsubo, T., Hasegawa, M., 2001. Calpain-mediated degradation of p35 to p25 in postmortem human and rat brains. FEBS Lett. 489, 4650. Taub, J., Lau, J.F., Ma, C., Hahn, J.H., Hoque, R., Rothblatt, J., Chale, M., 1999. A cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. Nature 399, 162166. Taylor, D.L., Diemel, L.T., Pocock, J.M., 2003. Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity. J. Neurosci. 23, 21502160. Tesco, G., Koh, Y.H., Tanzi, R.E., 2003. Caspase activation increases A beta generation independently of caspase cleavage of APP. J. Biol. Chem. 5, 5. Tetsu, O., McCormick, F., 1999. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422426. Thomas, C.C., Deak, M., Alessi, D.R., van Aalten, D.M., 2002. Highresolution structure of the pleckstrin homology domain of protein kinase b/akt bound to phosphatidylinositol (3,4,5)-trisphosphate. Curr. Biol. 12, 12561262. Tomiyama, T., Shoji, A., Kataoka, K., Suwa, Y., Asano, S., Kaneko, H., Endo, N., 1996. Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin: its possible function as a hydroxyl radical scavenger. J. Biol. Chem. 271, 68396844. Torriglia, A., Chaudun, E., Chany-Fournier, F., Jeanny, J.C., Courtois, Y., Counis, M.F., 1995. Involvement of DNase II in nuclear degeneration during lens cell differentiation. J. Biol. Chem. 270, 2857928585. Torriglia, A., Chaudun, E., Courtois, Y., Counis, M.F., 1997. On the use of Zn2+ to discriminate endonucleases activated during apoptosis. Biochimie 79, 435438. Touyarot, K., Poussard, S., Verret, C., Aragon, B., Cottin, P., Nogues, X., Micheau, J., 2000. Calpain-PKC inter-relations in mouse hippocampus: a biochemical approach. Neurochem. Res. 25, 781790. Town, T., Zolton, J., Shaffner, R., Schnell, B., Crescentini, R., Wu, Y., Zeng, J., DelleDonne, A., Obregon, D., Tan, J., Mullan, M., 2002. p35/Cdk5 pathway mediates soluble amyloid-beta peptide-induced tau phosphorylation in vitro. J. Neurosci. Res. 69, 362372. Troy, C.M., Rabacchi, S.A., Friedman, W.J., Frappier, T.F., Brown, K., Shelanski, M.L., 2000. Caspase-2 mediates neuronal cell death induced by beta-amyloid. J. Neurosci. 20, 13861392. Tyurin, V.A., Tyurina, Y.Y., Borisenko, G.G., Sokolova, T.V., Ritov, V.B., Quinn, P.J., Rose, M., Kochanek, P., Graham, S.H., Kagan, V.E., 2000. Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates. J. Neurochem. 75, 21782189. Uchiyama, T., Engelman, R.M., Maulik, N., Das, D.K., 2004. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning. Circulation 109, 30423049. Ulus, I.H., Wurtman, R.J., 1997. Metabotropic glutamate receptor agonists increase release of soluble amyloid precursor protein derivatives from rat brain cortical and hippocampal slices. J. Pharmacol. Exp. Ther. 281, 149154. Valla, J., Berndt, J.D., Gonzalez-Lima, F., 2001. Energy hypometabolism in posterior cingulate cortex of Alzheimers patients: supercial laminar
Sordella, R., Bell, D.W., Haber, D.A., Settleman, J., 2004. Getinibsensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 11631167. Soriano, S., Kang, D.E., Fu, M., Pestell, R., Chevallier, N., Zheng, H., Koo, E.H., 2001. Presenilin 1 negatively regulates beta-catenin/T cell factor/lymphoid enhancer factor-1 signaling independently of betaamyloid precursor protein and notch processing. J. Cell Biol. 152, 785794. Sriram, K., Pai, K.S., Boyd, M.R., Ravindranath, V., 1997. Evidence for generation of oxidative stress in brain by MPTP: in vitro and in vivo studies in mice. Brain Res. 749, 4452. Staal, S.P., 1987. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplication of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl. Acad. Sci. U.S.A. 84, 5034 5037. Staal, S.P., Huebner, K., Croce, C.M., Parsa, N.Z., Testa, J.R., 1988. The AKT1 proto-oncogene maps to human chromosome 14, band q32. Genomics 2, 9698. Stegh, A.H., Barnhart, B.C., Volkland, J., Algeciras-Schimnich, A., Ke, N., Reed, J.C., Peter, M.E., 2002. Inactivation of caspase-8 on mitochondria of Bcl-xL-expressing MCF7-Fas cells: role for the bifunctional apoptosis regulator protein. J. Biol. Chem. 277, 43514360. Stephens, L., Anderson, K., Stokoe, D., Erdjument-Bromage, H., Painter, G.F., Holmes, A.B., Gaffney, P.R., Reese, C.B., McCormick, F., Tempst, P., Coadwell, J., Hawkins, P.T., 1998. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279, 710714. Subramaniam, R., Koppal, T., Green, M., Yatin, S., Jordan, B., Drake, J., Buttereld, D.A., 1998. The free radical antioxidant Vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide(2535) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimers disease. Neurochem. Res. 23, 1403 1410. Suhara, T., Mano, T., Oliveira, B.E., Walsh, K., 2001. Phosphatidylinositol 3-kinase/Akt signaling controls endothelial cell sensitivity to Fasmediated apoptosis via regulation of FLICE-inhibitory protein (FLIP). Circ. Res. 89, 1319. Sun, X.M., Cohen, G.M., 1994. Mg2+-dependent cleavage of DNA into kilobase pair fragments is responsible for the initial degradation of DNA in apoptosis. J. Biol. Chem. 269, 1485714860. Susin, S.A., Lorenzo, H.K., Zamzami, N., Marzo, I., Snow, B.E., Brothers, G.M., Mangion, J., Jacotot, E., Costantini, P., Loefer, M., Larochette, N., Goodlett, D.R., Aebersold, R., Siderovski, D.P., Penninger, J.M., Kroemer, G., 1999. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441446. Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., Tsukamoto, Y., Iso, H., Fujimori, Y., Stern, D.M., Naritomi, H., Matsuyama, T., 2004. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J. Clin. Invest. 114, 330338. Takahashi, H., Nakamura, S., Asano, K., Kinouchi, M., Ishida-Yamamoto, A., Iizuka, H., 1999. Fas antigen modulates ultraviolet B-induced apoptosis of SVHK cells: sequential activation of caspases 8, 3, and 1 in the apoptotic process. Exp. Cell Res. 249, 291298. Takashima, A., Honda, T., Yasutake, K., Michel, G., Murayama, O., Murayama, M., Ishiguro, K., Yamaguchi, H., 1998a. Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (2535) enhances phosphorylation of tau in hippocampal neurons. Neurosci. Res. 31, 317323. Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., Nihonmatsu, N., Mercken, M., Yamaguchi, H., Sugihara, S., Wolozin, B., 1998b. Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. U.S.A. 95, 96379641. Takashima, A., Noguchi, K., Sato, K., Hoshino, T., Imahori, K., 1993. Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 90, 77897793.
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 cytochrome oxidase associated with disease duration. J. Neurosci. 21, 49234930. van de Craen, M., de Jonghe, C., van den Brande, I., Declercq, W., van Gassen, G., van Criekinge, W., Vanderhoeven, I., Fiers, W., van Broeckhoven, C., Hendriks, L., Vandenabeele, P., 1999. Identication of caspases that cleave presenilin-1 and presenilin-2. Five presenilin-1 (PS1) mutations do not alter the sensitivity of PS1 to caspases. FEBS Lett. 445, 149154. Vanags, D.M., Porn-Ares, M.I., Coppola, S., Burgess, D.H., Orrenius, S., 1996. Protease involvement in fodrin cleavage and phosphatidylserine exposure in apoptosis. J. Biol. Chem. 271, 3107531085. Varadarajan, S., Yatin, S., Kanski, J., Jahanshahi, F., Buttereld, D.A., 1999. Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res. Bull. 50, 133141. Varfolomeev, E.E., Schuchmann, M., Luria, V., Chiannilkulchai, N., Beckmann, J.S., Mett, I.L., Rebrikov, D., Brodianski, V.M., Kemper, O.C., Kollet, O., Lapidot, T., Soffer, D., Sobe, T., Avraham, K.B., Goncharov, T., Holtmann, H., Lonai, P., Wallach, D., 1998. Targeted disruption of the mouse caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9, 267 276. Vaudry, D., Pamantung, T.F., Basille, M., Rousselle, C., Fournier, A., Vaudry, H., Beauvillain, J.C., Gonzalez, B.J., 2002. PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur. J. Neurosci. 15, 14511460. Vaziri, H., Dessain, S.K., Ng Eaton, E., Imai, S.I., Frye, R.A., Pandita, T.K., Guarente, L., Weinberg, R.A., 2001. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149159. Verhagen, A.M., Ekert, P.G., Pakusch, M., Silke, J., Connolly, L.M., Reid, G.E., Moritz, R.L., Simpson, R.J., Vaux, D.L., 2000. Identication of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 102, 4353. Vielhaber, S., Kunz, D., Winkler, K., Wiedemann, F.R., Kirches, E., Feistner, H., Heinze, H.J., Elger, C.E., Schubert, W., Kunz, W.S., 2000. Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 123 (Pt 7), 13391348. Vincent, A.M., Maiese, K., 1999a. Direct temporal analysis of apoptosis induction in living adherent neurons. J. Histochem. Cytochem. 47, 661 672. Vincent, A.M., Maiese, K., 1999b. Nitric oxide induction of neuronal endonuclease activity in programmed cell death. Exp. Cell Res. 246, 290300. Vincent, A.M., Maiese, K., 2000. The metabotropic glutamate system promotes neuronal survival through distinct pathways of programmed cell death. Exp. Neurol. 166, 6582. Vincent, A.M., Mohammad, Y., Ahmad, I., Greenberg, R., Maiese, K., 1997. Metabotropic glutamate receptors prevent nitric oxide-induced programmed cell death. J. Neurosci. Res. 50, 549564. Vincent, A.M., TenBroeke, M., Maiese, K., 1999. Metabotropic glutamate receptors prevent programmed cell death through the modulation of neuronal endonuclease activity and intracellular pH. Exp. Neurol. 155, 7994. Volbracht, C., Fava, E., Leist, M., Nicotera, P., 2001. Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis. Neuroreport 12, 36453648. Wagner, U., Brownlees, J., Irving, N.G., Lucas, F.R., Salinas, P.C., Miller, C.C., 1997. Overexpression of the mouse dishevelled-1 protein inhibits GSK-3beta-mediated phosphorylation of tau in transfected mammalian cells. FEBS Lett. 411, 369372. Walker, K.S., Deak, M., Paterson, A., Hudson, K., Cohen, P., Alessi, D.R., 1998. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem. J. 331 (Pt 1), 299308. Walton, M., Woodgate, A.M., Muravlev, A., Xu, R., During, M.J., Dragunow, M., 1999. CREB phosphorylation promotes nerve cell survival. J. Neurochem. 73, 18361842.
245
Wang, C.Y., Mayo, M.W., Korneluk, R.G., Goeddel, D.V., Baldwin Jr., A.S., 1998. NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and cIAP1 and c-IAP2 to suppress caspase-8 activation. Science 281, 1680 1683. Wang, J.Y., Shum, A.Y., Ho, Y.J., 2003. Oxidative neurotoxicity in rat cerebral cortex neurons: synergistic effects of H2O2 and NO on apoptosis involving activation of p38 mitogen-activated protein kinase and caspase-3. J. Neurosci. Res. 72, 508519. Wang, N., Verna, L., Hardy, S., Zhu, Y., Ma, K.S., Birrer, M.J., Stemerman, M.B., 1999. c-Jun triggers apoptosis in human vascular endothelial cells. Circ. Res. 85, 387393. Wang, R., Zhang, H.Y., Tang, X.C., 2001. Huperzine A attenuates cognitive dysfunction and neuronal degeneration caused by beta-amyloid protein(140) in rat. Eur. J. Pharmacol. 421, 149156. Wang, X., McCullough, K.D., Franke, T.F., Holbrook, N.J., 2000. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J. Biol. Chem. 275, 1462414631. Watson, A., Eilers, A., Lallemand, D., Kyriakis, J., Rubin, L.L., Ham, J., 1998. Phosphorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons. J. Neurosci. 18, 751762. Weber, J., 2004. Calcium homeostasis following traumatic neuronal injury. Curr. Neurovasc. Res. 1, 151171. Wegiel, J., Wang, K.C., Tarnawski, M., Lach, B., 2000. Microglia cells are the driving force in brillar plaque formation, whereas astrocytes are a leading factor in plague degradation. Acta Neuropathol. (Berl.) 100, 356364. Wehrli, M., Dougan, S.T., Caldwell, K., OKeefe, L., Schwartz, S., VaizelOhayon, D., Schejter, E., Tomlinson, A., DiNardo, S., 2000. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527530. Wen, T.C., Sadamoto, Y., Tanaka, J., Zhu, P.X., Nakata, K., Ma, Y.J., Hata, R., Sakanaka, M., 2002. Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J. Neurosci. Res. 67, 795803. Wen, Y., Yang, S., Liu, R., Brun-Zinkernagel, A.M., Koulen, P., Simpkins, J.W., 2004. Transient cerebral ischemia induces aberrant neuronal cell cycle re-entry and Alzheimers disease-like tauopathy in female rats. J. Biol. Chem. 279, 2268422692. Whiteld, J., Neame, S.J., Paquet, L., Bernard, O., Ham, J., 2001. Dominant-negative c-Jun promotes neuronal survival by reducing BIM expression and inhibiting mitochondrial cytochrome c release. Neuron 29, 629643. Wick, A., Wick, W., Waltenberger, J., Weller, M., Dichgans, J., Schulz, J.B., 2002. Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J. Neurosci. 22, 64016407. Wick, M.J., Dong, L.Q., Riojas, R.A., Ramos, F.J., Liu, F., 2000. Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J. Biol. Chem. 275, 4040040406. Wilson, F.H., Hariri, A., Farhi, A., Zhao, H., Petersen, K.F., Toka, H.R., Nelson-Williams, C., Raja, K.M., Kashgarian, M., Shulman, G.I., Scheinman, S.J., Lifton, R.P., 2004. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science 306, 1190 1194. Witthuhn, B.A., Quelle, F.W., Silvennoinen, O., Yi, T., Tang, B., Miura, O., Ihle, J.N., 1993. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell 74, 227236. Witting, A., Muller, P., Herrmann, A., Kettenmann, H., Nolte, C., 2000. Phagocytic clearance of apoptotic neurons by microglia/brain macrophages in vitro: involvement of lectin-, integrin-, and phosphatidylserine-mediated recognition. J. Neurochem. 75, 10601070. Wood, D.E., Thomas, A., Devi, L.A., Berman, Y., Beavis, R.C., Reed, J.C., Newcomb, E.W., 1998. Bax cleavage is mediated by calpain during drug-induced apoptosis. Oncogene 17, 10691078.
246
Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246 Yin, H., Chao, L., Chao, J., 2004. Adrenomedullin protects against myocardial apoptosis after ischemia/reperfusion through activation of AktGSK signaling. Hypertension 43, 109116. Yin, K.J., Lee, J.M., Chen, S.D., Xu, J., Hsu, C.Y., 2002a. Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. J. Neurosci. 22, 97649770. Yin, X.M., Luo, Y., Cao, G., Bai, L., Pei, W., Kuharsky, D.K., Chen, J., 2002b. Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia. J. Biol. Chem. 277, 4207442081. You, Z., Saims, D., Chen, S., Zhang, Z., Guttridge, D.C., Guan, K.L., MacDougald, O.A., Brown, A.M., Evan, G., Kitajewski, J., Wang, C.Y., 2002. Wnt signaling promotes oncogenic transformation by inhibiting cMyc-induced apoptosis. J. Cell Biol. 157, 429440. Youdim, M.B., Fridkin, M., Zheng, H., 2004. Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinsons disease and other neurodegenerative diseases. J. Neural. Transm. 111, 14551471. Zeiner, A., Sunder-Plassmann, G., Sterz, F., Holzer, M., Losert, H., Laggner, A.N., Mullner, M., 2004. The effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation in men. Resuscitation 60, 253261. Zhan, Q., Antinore, M.J., Wang, X.W., Carrier, F., Smith, M.L., Harris, C.C., Fornace Jr., A.J., 1999. Association with Cdc2 and inhibition of Cdc2/ cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18, 28922900. Zhang, J., Perry, G., Smith, M.A., Robertson, D., Olson, S.J., Graham, D.G., Montine, T.J., 1999. Parkinsons disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am. J. Pathol. 154, 14231429. Zhang, Y., McLaughlin, R., Goodyer, C., LeBlanc, A., 2002. Selective cytotoxicity of intracellular amyloid beta peptide 142 through p53 and Bax in cultured primary human neurons. J. Cell Biol. 156, 519529. Zhang, Z., Hartmann, H., Do, V.M., Abramowski, D., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., van de Wetering, M., Clevers, H., Saftig, P., De Strooper, B., He, X., Yankner, B.A., 1998. Destabilization of betacatenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395, 698702. Zheng-Fischhofer, Q., Biernat, J., Mandelkow, E.M., Illenberger, S., Godemann, R., Mandelkow, E., 1998. Sequential phosphorylation of tau by glycogen synthase kinase-3beta and protein kinase A at Thr212 and Ser214 generates the Alzheimer-specic epitope of antibody AT100 and requires a paired-helical-lament-like conformation. Eur. J. Biochem. 252, 542552. Zhu, D.Y., Deng, Q., Yao, H.H., Wang, D.C., Deng, Y., Liu, G.Q., 2002. Inducible nitric oxide synthase expression in the ischemic core and penumbra after transient focal cerebral ischemia in mice. Life Sci. 71, 19851996. Zigmond, M.J., Hastings, T.G., Perez, R.G., 2002. Increased dopamine turnover after partial loss of dopaminergic neurons: compensation or toxicity? Parkinsonism Relat. Disord. 8, 389393. Zou, H., Henzel, W.J., Liu, X., Lutschg, A., Wang, X., 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 90, 405413.
Wu, W.B., Peng, H.C., Huang, T.F., 2003. Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells: involvement of cellcell and cellECM interactions in regulating cell viability. Exp. Cell Res. 286, 115127. Xu, X., Shi, Y.C., Gao, W., Mao, G., Zhao, G., Agrawal, S., Chisolm, G.M., Sui, D., Cui, M.Z., 2002. The novel presenilin-1-associated protein is a proapoptotic mitochondrial protein. J. Biol. Chem. 277, 4891348922. Yaffe, M.B., Rittinger, K., Volinia, S., Caron, P.R., Aitken, A., Leffers, H., Gamblin, S.J., Smerdon, S.J., Cantley, L.C., 1997. The structural basis for 1433:phosphopeptide binding specicity. Cell 91, 961971. Yager, J.Y., Asselin, J., 1996. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke 27, 919925, discussion 926. Yamagishi, S., Matsumoto, T., Yokomaku, D., Hatanaka, H., Shimoke, K., Yamada, M., Ikeuchi, T., 2003. Comparison of inhibitory effects of brain-derived neurotrophic factor and insulin-like growth factor on low potassium-induced apoptosis and activation of p38 MAPK and c-Jun in cultured cerebellar granule neurons. Brain Res. Mol. Brain Res. 119, 184191. Yamaguchi, H., Wang, H.G., 2001. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene 20, 77797786. Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M.P., Mitsuda, N., Tohyama, M., 2001. Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J. Biol. Chem. 276, 52565264. Yamamoto, H., Kishida, S., Kishida, M., Ikeda, S., Takada, S., Kikuchi, A., 1999. Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability. J. Biol. Chem. 274, 1068110684. Yamamoto, K., Katayose, Y., Suzuki, M., Unno, M., Sasaki, T., Mizuma, M., Shiraso, S., Ohtuka, H., Cowan, K.H., Seth, P., Matsuno, S., 2003. Adenovirus expressing p27KIP1 induces apoptosis against cholangiocarcinoma cells by triggering Fas ligand on the cell surface. Hepatogastroenterology 50, 18471853. Yamamoto, T., Maruyama, W., Kato, Y., Yi, H., Shamoto-Nagai, M., Tanaka, M., Sato, Y., Naoi, M., 2002. Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells. J. Neural. Transm. 109, 113. Yamato, M., Egashira, T., Utsumi, H., 2003. Application of in vivo ESR spectroscopy to measurement of cerebrovascular ROS generation in stroke. Free Radic. Biol. Med. 35, 16191631. Yang, J., Cron, P., Thompson, V., Good, V.M., Hess, D., Hemmings, B.A., Barford, D., 2002. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol. Cell 9, 1227 1240. Yang, Y., Mufson, E.J., Herrup, K., 2003. Neuronal cell death is preceded by cell cycle events at all stages of Alzheimers disease. J. Neurosci. 23, 25572563. Yano, S., Morioka, M., Fukunaga, K., Kawano, T., Hara, T., Kai, Y., Hamada, J., Miyamoto, E., Ushio, Y., 2001. Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subeld of gerbil hippocampus. J. Cereb. Blood Flow Metab. 21, 351360.

Oxidative Stress in The Brain Novel Cellular Targets That Govern 2005

Încărcat de

Informații document

Descriere originală:

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Oxidative Stress in The Brain Novel Cellular Targets That Govern 2005

Încărcat de

Drepturi de autor:

Formate disponibile

Progress in Neurobiology 75 (2005) 207246 www.elsevier.

Received 29 July 2004; accepted 16 February 2005

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Parkinsons disease Huntingtons disease

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

Z.Z. Chong et al. / Progress in Neurobiology 75 (2005) 207246

S-ar putea să vă placă și