Alzheimer's Disease

and the
Mitochondria

Felicia Leung, Manmohit Gill, Jonathan Tsou, Han Nguyen 1

 Alzheimer’s Disease (AD)

● Neurodegenerative disorder
● 2 types: early & late onset
● Progressive disease
● Symptoms: learning deficits, memory
loss, confusion, trouble with once
familiar tasks

2
Amyloid Precursor Protein (APP)

● Large membrane protein

● Role in neural growth and repair
● Sends signals through G protein system
● Binds to structural molecules

3
 Amyloid Beta Plaques

● Amyloid beta formed from proteolysis

of APP by secretases
● Normally, protein fragments broken
down and eliminated
● In those with AD, fragments
accumulate to form hard, insoluble
plaques

4
Tau Proteins-Neurofibrillary Tangles

● Stabilization of microtubules
● In those with AD, abnormal
accumulations of tau protein
(neurofibrillary tangles)
● Symptoms of AD shown to
correlate with accumulation of
plaques and tangles
● Amyloid beta and tau proteins used
as biomarkers

5
 Mitochondria: The Powerhouse of the Cell

● Surrounded by two membranes and has its own genome

● Divides independently from the cell in which it resides
in
● Generates ATP at a rate of 4.7bn ATP/second per
cortical neuron
● ATP used in the CNS for: synaptic transmission, action
potential, formation of synapses, neuronal branching
and growth
● Neurons highly rely on the function of mitochondria

6
Mitochondrial DNA (mtDNA)

● mtDNA contains 37 genes - 13 of the genes code for making

enzymes involved in oxidative phosphorylation while the others
code for the production of rRNA and tRNA
● No histones on mtDNA
● Exhibits maternal inheritance
● Heteroplasmy can occur

7
Reactive Oxygen Species (ROS) are
Produced by the Mitochondria

● ROS are a component of the killing response of the immune

system to microbial invasion
● Most ROS are formed as byproducts during mitochondrial ETC
of aerobic respiration
● ROS are necessary intermediates of metal catalyzed oxidation
reactions
● Recent studies indicate ROS act as messengers in normal cell
signal transduction and cell cycling

8
Mitochondrial Generation of Reactive
Oxygen Species (ROS)

● ETC generates ATP when NADH donates

electrons
● ROS such as a superoxide radical forms when
the donated electrons escape and combine
with oxygen
● Superoxide radical is a proximal mitochondrial
ROS that is destructive to cellular components

9
 Protection from Superoxide

● Our bodies contain superoxide dismutase

(SOD) to reduce superoxide to H2O2
● Catalase then converts H2O2 to water
and oxygen

10
Mitochondria dysfunction in patients with
Alzheimer’s Disease (Outline)
Point 1: Associating AD pathology with mitochondria

● The mechanism by which amyloid beta is introduced into the mitochondria

Point 2: The effects of ROS in neurodegenerative disease (NDD)

● How DNA damage leads to apoptosis

● The Electron Transport Chain (ETC) enzymes implicated in AD or ROS overproduction
● ROS cause cytokines to be released from neurons to activate microglia and astrocytes

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Q: How does Amyloid Beta enter the
mitochondria? (Point 1)
Q: How does Amyloid Beta enter the
mitochondria? (Point 1)

● APP is transported by the translocase of

outer membrane (TOM) Complex and
the translocase of inner membrane
(TIM) complex.
● TOM: 3 receptors (Tom20, 22, 70), and
1 pore (Tom40).
● In rats, neutralizing antibodies against
receptor proteins led to reduced
transport of amyloid beta (abeta).

13
Mitochondria and AD patients (Introduction)
Point 1:

● amyloid beta is introduced into the mitochondria by APP protein-transport mediated by

TOM and TIM (1, ref40)

Point 2: The effects of ROS in neurodegenerative disease (NDD)

● How DNA damage leads to apoptosis

● The Electron Transport Chain (ETC) enzymes implicated in AD or ROS overproduction
● ROS cause cytokines to be released from neurons to activate microglia and astrocytes

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Priming Questions (Point 2)
DNA-damage and Apoptosis

● How does oxidative stress lead to DNA damage and apoptosis?

ETC dysfunction

● Are there any defects in ETC enzymes known to be associated with AD?

Neuroinflammation

● What cytokines are released by neurons in NDD that cause neuroinflammation?

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How does oxidative stress lead to DNA
damage and apoptosis?

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How does oxidative stress lead to DNA
damage and apoptosis?

dsDNA break

→ P53 stimulated

→ alter regulation
of BCL2 family (e.g.
antiapoptotic
BCL-XL
downregulated)

→ upregulation of
caspases 3, 6, 7.

→ apoptosis
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Are there any defects in ETC enzymes
known to be associated with AD?
But,
● mtDNA damage → complex 1, complex
3 defects → O2- formed 4
● NO modifies activity of complex 1 and 4
(interferes with Fe-S centre) 5
● No causative mutations linked to AD
currently known 1
● Complex 4 mutations found in AD
patients 1
● Replacing mitochondria with mtDNA
from AD patients → amyloid beta
overproduction, susceptibility to
apoptosis 2
● Pathogenic mtDNA in a variety of
cognitive disorders 3
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Are there any defects in ETC enzymes
known to be associated with AD?
But,
● mtDNA damage → complex 1, complex
3 defects → O2- formed 4
● NO modifies activity of complex 1 and 4
(interferes with Fe-S centre) 5
● No causative mutations linked to AD
currently known 1
● Complex 4 mutations found in AD
patients 1
● Replacing mitochondria with mtDNA
from AD patients → amyloid beta
overproduction, susceptibility to
apoptosis 2
● Pathogenic mtDNA in a variety of
cognitive disorders 3
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Which cytokines are released by neurons and
act on microglia to cause neuroinflammation?

● ROS → release IL-1beta, IL-6, TNF-alpha

(nitric oxide also acts on immune cells) 1
● → More ROS, chronic inflammation →
neuron loss 2
● Neuroinflammation increases NFT
formation 3

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Which cytokines are released by neurons and
act on microglia to cause neuroinflammation?

● ROS → release IL-1beta, IL-6, TNF-alpha

(nitric oxide also acts on immune cells) 1
● → More ROS, chronic inflammation →
neuron loss 2
● Neuroinflammation increases NFT
formation 3

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Mitochondria dysfunction in patients with
Alzheimer’s Disease (Summary)

Point 1:

● Amyloid beta is introduced into the mitochondria by APP protein-transport mediated by

TOM and TIM (1, ref40)

Point 2:

● Apoptosis may be mediated by P53, BCL-2 proteins, caspases 3, 6 and 7.

● There are currently no known mutations in ETC proteins linked to AD, but ROS lead to
mutations or modify the activity of Complexes 1, 3 and 4
● ROS causes the release of cytokines IL-1beta, IL-6, TNF-alpha to be released from
neurons to activate microglia and astrocytes

22
 Pharmacology/Treatments

- Cholinesterase inhibitors
- donepezil, rivastigmine, and galantamine
- N-methyl-D-aspartate antagonist
- memantine
- SSRIs, Serotonin Reuptake Inhibitors
- fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine
- TCA, Tricyclic Antidepressants
- desipramine, nortriptyline
- SNRIs, Selective Norepinephrine Reuptake Inhibitors
- mirtazapine, venlafaxine, duloxetine
- Benzodiazepine
- lorazepam, oxazepam, temazepam, olanzapine
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The Amyloid Hypothesis of Alzheimer’s
Disease
To block the progression of the disease they have to interfere with
the pathogenic steps responsible for the clinical symptoms:
- Deposition of extracellular amyloid β plaques and intracellular
neurofibrillary tangle formation
- Inflammation
- Oxidative damage
- Iron deregulation
- Cholesterol metabolism

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Summary
● AD is the progressive degeneration and/or death of nerve cells
● Symptoms include learning deficits, memory loss, confusion
● Amyloid beta formed from proteolysis of APP by secretases, accumulate to form plaques
● Abnormal accumulations of tau protein called neurofibrillary tangles
● Symptoms of AD shown to correlate with accumulation of plaques and tangles
● ROS is formed when the electrons donated to the ETC by NADH during aerobic respiration
escapes and combines with oxygen
● SOD reduces superoxide to form H2O2 which is then converted to water and oxygen by catalase
● ROS causes the release of cytokines IL-1beta, IL-6, TNF-alpha to be released from neurons to
activate microglia and astrocytes
● Amyloid beta is introduced into the mitochondria by APP protein-transport mediated by TOM
and TIM
● Apoptosis may be mediated by P53, BCL-2 proteins, caspases 3, 6 and 7.
● There are currently no known mutations in ETC proteins linked to AD, but ROS lead to mutations
or modify the activity of Complexes 1, 3 and 4
● Current treatments include cholinesterase inhibitors, NMDA antagonists, and
antipsychotics/antidepressants, with further research to block the progression of the disease at a
biochemical level

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