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Inflammation in Dry Age-Related Macular Degeneration Eduardo B.

Rodrigues Retina Department, Ophthalmology Service, Hospital Regional So Jos, nstituto de Olhos !lorian"polis#$entro O%talmol"gico, !lorian"polis, Bra&il 'ddress o% $orresponding 'uthor Ophthalmologica ())*+((,-,./0,1( 2DO - ,).,,13#))))33(3/4 Outline

5ey 6ords '7stract ntroduction Historical 'spect n%lammation in Early 'R8D 0 Etiology o schemia o 9enetics o :hoto0O;idative Stress o Hydrodynamic 'lterations in Bruch<s 8em7rane and R:E o 'utoimmunity o R:E =rans%ormation o De7ris 'ccumulation under the R:E Space and >ipoprotein =o;icity Drusen :lasma0Derived ?asoactive 8ediators o% n%lammation $ell0Derived 8ediators o% n%lammation o '' and :latelet0'ctivating !actors o :eptides, $yto@ines and $hemo@ines in Early 'R8D 'cute0:hase Response and Regulatory :roteins in Drusen $omplement System 'ctivation mmunoglo7ulin and mmune $omple; n%lammatory $ells Drusen Deposits 'nalogous to 'ge0Related Aeurological and $ardiac Disease !inal $onsiderations 'c@noBledgments Re%erences 'uthor $ontacts 'rticle n%ormation :u7lication Details Drug Dosage # $opyright

Key Words

'ge0related macular degeneration, in%lammation ?ascular endothelial groBth %actor

Abstract Purpose: =o summari&e the current in%ormation regarding the role o% immune and in%lammatory response in the pathogenesis o% dry age0related macular degeneration 2'R8D4. Methods: ' :u7med search Bas conducted o% the period January ,333 to ())1. Relevant in%ormation in the literature on the role o% in%lammation in early dry 'R8D Bas revieBed. Results: Some important evidence %or in%lammation in early 'R8D consists in the isolation o% immunoglo7ulins, complement proteins, cyto@ines and activated microglia, in retinal pigment epithelium 2R:E4 cells and drusen. :ivotal mechanisms in early 'R8D include the accumulation o% de7ris and proteins along the R:E sur%ace, %olloBed 7y immune0comple; deposition and complement activation. n contrast, the role o% other plasma en&ymes such as @alli@rein0@inin07rady@inin, the Hageman %actor, peptides and coagulation proteins in drusen %ormation and 'R8D has yet to 7e determined. Conclusion: ' clear role %or in%lammatory mediators and cells has 7een esta7lished in recent years. !uture studies should elucidate %urther mechanisms in 'R8D development. $opyright C ())* S. 5arger '9, Basel

Introduction 'ge0related macular degeneration 2'R8D4 is a leading cause o% 7lindness in older patients in the Bestern Borld D,E. =he clinical %eatures consist in drusen, retinal pigment epithelium 2R:E4 alterations, geographic atrophy and choroidal neovasculari&ation 2$A?4 that ultimately lead to photoreceptor damage D(E. =he clinical %indings result %rom aging changes that modi%y the 7iochemical structure and histology in the retina and choroid D/E. 8aFor pathogenic %actors in the %ormation o% 'R8D include ischemia, o;idative stress and local production o% angiogenic %actors. HoBever, evidence has also pointed to immunological and in%lammatory %actors contri7uting to disease %ormation. 's any Bound0healing response in the 7ody, the pathogenesis o% 'R8D is su7divided into 2a4 in%lammatory, 274 proli%erative and 2c4 remodeling phases. =he in%lammatory stage should evolve in the early asymptomatic and dry drusenoid stages as Bell as the early stages o% $A?. =he proli%erative and remodeling phases may 7e represented 7y the late $A? %ormation and the disci%orm scar process, respectively. nterestingly, aging and the secondary in%lammatory arrest have 7een associated Bith numerous degenerative disorders including 'l&heimer<s disease 2'D4, :ar@inson<s disease and atherosclerosis D.E. =his paper summari&es the current in%ormation o% immunity and in%lammation in dry early 'R8D.

Historical Aspect =he in%lammatory and immune processes in 'R8D Bere recogni&ed in ,G*1, Bhen :agenstecher and 9enth D1E proposed clinical in%lammation in neovascular 'R8D, con%irmed 7y su7seHuent studies at the 7eginning o% the ()th century DI, *E. nterestingly, the in%lammatory hypothesis remained dormant until several decades later. n the seventies 9reen and 5ey DGE %ocused on postmortem histology to con%irm in%lammatory mechanisms in the pathogenesis o% 'R8D. =he recent progress in molecular 7iology and the introduction o% su7retinal surgery cataly&ed the research on the patho7iology o% 'R8D D3, ,)E.

Inflammation in Early ARMD - Etiology 'R8D is a comple; 7iological process associated Bith alteration in en&yme#genetic systems and accumulation o% Baste materials. 'nother %eature is deposition o% in%lammatory mediators Bhich could initiate su7retinal chronic in%lammation and drusen %ormation. =here are several theories that in com7ination may e;plain the 7eginning o% drusen %ormation and 'R8D 2%ig. ,4.

Fig ! =heoretical etiological mechanisms in the %ormation o% 'R8D.

Isc"emia =he macular photoreceptors consume 3)J o% the o;ygen delivered 7y the choriocapillaries, there7y creating a su7retinal environment o% limited nutrients#o;ygen. Su7retinal ischemia may 7e %urther precipitated 7y diminished choroidal 7lood %loB or the deposit o% lipids#proteins. Some studies shoBed in 'R8D patients numerous choroidal de%ects on %luorescein angiography and a diminished pulse#amplitude o% 7lood %loB D,,, ,(E. #enetics =he theory o% a genetic cause o% 'R8D has 7een supported 7y tBin concordance, 7iomolecular and lin@age investigations. 'R8D in a %irst0degree relative enhances the chance o% disease 7y / times, and mono&ygotic tBins have 7een associated Bith a 3)J ris@ o% concordance D,/, ,.E. ' recent study determined tBo single0nucleotide polymorphisms 2SA:s4 related to 'R8D, the result is a /0 to *0%old ris@ o% developing 'R8D D,1E.

$"oto-O%idati&e 'tress =he photo0o;idative damage to the retina may occur secondary to- 2a4 release o% reactive o;ygen intermediates, 274 impaired antio;idative retinal protection in elderly individuals or 2c4 intracellular generation o% phototo;icity 7y lipo%uscin that leads to rupture o% R:E %unction. =hese com7ined mechanisms may induce sustained su7retinal o;idative stress that damages cell %unction 7y apoptosis or necrosis D,IE. Hydrodynamic Alterations in (ruc")s Membrane and R$E =he delicate position o% Bruch<s mem7rane serves as a mechanical#%unctional 7arrier %or retinal homeostasis. n older patients, Bruch<s mem7rane undergoes an increase in morphological thic@ness due to calci%ication o% the elastic layer. n 'R8D patients, the decline in hydraulic conductivity o% Bruchs< mem7rane diminishes R:E conductivity in lipid#collagen meta7olism Bhich may stimulate macrophage0induced in%lammation D,), ,IE. Autoimmunity !urther immunological evidence in the patho7iology o% early 'R8D arises %rom o7servations o% speci%ic autoimmunity. $onsecutive studies have shoBn that sera o% 'R8D patients disclosed a high amount o% antiretinal autoanti7odies, e.g. antiastrocyte anti7odies D,*, ,GE. HoBever, healthy controls have 7een %ound to possess autoanti7odies to retinal elements, and the role o% autoimmunity remains to 7e clari%ied D,3E. R$E *ransformation ' strong evidence in the literature points toBards the R:E dys%unction as an important primary mechanism in the pathogenesis o% 'R8D. Researches 7y Hagemann, 'nderson and coBor@ers revealed a su7population o% R:E cells that contain several morphological characteristics and proteins 2$0reactive protein, $R:, g9, apolipoprotein E4 o%ten present in drusen. =he reason %or R:E trans%ormation may involve R:E cell reaction to inFury or to;icity D(),(,,((E. Debris Accumulation under t"e R$E 'pace and +ipoprotein *o%icity One @ey morphological a7normality in 'R8D ta@es place in the space 7etBeen Bruch<s mem7rane and the R:E. :hospholipids, neutral %ats and the transporter apolipoproteins B and E have 7een isolated 7eloB the R:E, and such an accumulation may prevent a normal %lu; o% solute#%luid through the R:E, %undamental %or cell survival D((, (/E. 8oreover, such su70R:E accumulation and conseHuent de7ris %ormation could generate an in%lammatory reaction. !urther studies should clari%y i% su70R:E deposits play an o7ligatory role in the %ormation o% early drusen and the e;act 7iochemical pathBay %or the disease.

Drusen Drusen consist in e;tracellular deposits 7etBeen the R:E and Bruch<s mem7rane, a morphological mani%estation o% either R:E or photoreceptor disease. =he %ormation o% drusen is an active process Bith distinct 7iological pathBays, including in%lammatory and immune0mediated processes. =he spectrum o% in%lammatory mediators in early 'R8D consists in prostaglandins, complement, cyto@ines, chemo@ines, proteases, adhesion molecules, proteins, lipids and %ree radicals D(.,(1,(I,(*,(G,(3,/),/,,/(,//E. mmunohistochemical studies o% drusen have identi%ied ultrastructural elements such as %i7ronectin, u7iHuitin, vitronectin, laminin, al7umin, integrins, collagens, amyloid, tissue inhi7itor o% metalloproteinase /, apolipoprotein E, calcium, complement components, advanced glycation end products and heparin sul%ate D,(, /.E. Drusen are also immunoreactive %or immunoglo7ulins and components o% the complement pathBay related to immune0comple; deposition. Johnson et al. D /)E proposed that drusen 7iogenesis occurs a%ter a primary R:E dys%unction that leads to an in%lammatory response, activates the complement cascade and %inally evo@es an R:E0related immune response. =he su70R:E accumulation o% proteins, lipids, organelles and R:E cell %ragments in drusen %ormation provides a strong proin%lammatory signal leading to the %olloBing events D(,E 2ta7le ,4-

*able ! 8olecular mediators and cellular elements isolated to date in drusen and early 'R8D development

0 e;pression and release o% cyto@ines, acute0phase reactants and other proin%lammatory mediators+ 0 activation o% the complement cascade+ 0 stimulation o% a protective response to complement attac@ 7y the R:E and other local cells+ 0 R:E degeneration+ 0 dendritic cell migration into drusen+ 0 induction o% immune response to e;posed antigens o% the R:E environment.

$lasma-Deri&ed ,asoacti&e Mediators of Inflammation

:lasma0derived vasoactive mediators o% in%lammation may originate %rom circulating cellular elements including platelets, leu@ocytes and inFured tissues. =hey may arise via / 7iochemical pathBays- 2a4 meta7olism o% arachidonic acid 2''+ prostaglandins, throm7o;anes, leu@otrienes, lipo;ins, platelet0activating %actor4, 274 cytoplasmic granules 2histamine, serotonin4 and 2c4 normal regulators o% vascular %unction 2nitric o;ide and neuro@inins4. =o act on the in%lammatory processes, the plasma mediators o% in%lammation act through / en&yme cascades o% proteases2,4=he Hageman factor 2%actor K 4 is activated 7y e;posure to negatively charged sur%aces such as 7asement mem7ranes and proteolytic en&ymes. =he release o% Hageman %actor results in 2a4 conversion o% plasminogen to plasmin, 274 conversion o% pre@alli@rein to @alli@rein to %orm @inins, 2c4 activation o% the alternative complement pathBay and 2d4 activation o% the coagulation system. 6hile the products o% Hageman %actor activation such as complement proteins have 7een correlated Bith drusen D/1E, there is no clear study to determine its direct participation in the disease. 2(4 =he coagulation cascade, through the intrinsic and e;trinsic pathBays, converts prothrom7in to throm7in, Bhich activates %i7rin %rom %i7rinogen. =hrom7in participates in endothelial cell %unctions, leu@ocyte adhesion and the increase in endothelial permea7ility. n patients Bith 'R8D, plasma %i7rinogen and ceruloplasmin levels have 7een %ound to 7e higher than in controls D/IE. 8oreover, %i7rinogen, throm7in and prothrom7in Bere immunolocali&ed in di%%erent margins o% drusen D(,, (I, (*E. 6hereas a correlation o% coagulation Bith in%lammation has 7een esta7lished %or other deposit diseases such as atherosclerosis, their e;act role in 'R8D patho7iology has yet to 7e determined. 2/4 =he kallikrein-kinin-bradykinin system participates in the ampli%ication o% the in%lammatory response 7y interacting Bith tissue and in%lammatory cells to produce chemical mediators such as cyto@ines and nitric o;ide. =he active molecules include 7rady@inin and its related peptides, Bhich regulate 7lood pressure#local 7lood %loB, vasodilatation and stimulation o% cell proli%eration. =hey are e;pressed in retinal cells, including the outer nuclear layer, inner nuclear layer and ganglion cell layer, and endothelial cells D/*E. ' @alli@rein07inding protein has 7een shoBn to inhi7it retinal neovasculari&ation and to decrease vascular lea@age D/GE. =he involvement o% the @alli@rein0@inin system in early 'R8D has not 7een studied yet.

-ell-Deri&ed Mediators of Inflammation AA and $latelet-Acti&ating Factors :hospholipids and %atty acid derivates released %rom plasma mem7ranes are meta7oli&ed into mediators o% in%lammatory cells in tBo pathBays, the '' and platelet0activating %actor ones. :latelet0activating %actor has stimulatory e%%ects on platelets, neutrophils, macrophages and endothelial cells, so %ar not correlated Bith 'R8D. '' elements,

produced 7y tBo en&ymatic systems 2phosphatidylinositol#phosphatidylcholine and cycloo;ygenase#lipo;ygenase4, generate mediators o% in%lammation such as leu@otrienes 2>='., >=B., >=$., >=D., >=E.4, lipo;ins 2>K'., >KB., ,10epi0>K4 and prostanoids 2:9 (, :9D(, :9E(, :9!( 4. =he mammalian retina contains large amounts o% '' derivates involved in retinal neurotransmission and cell0to0cell interaction. nvestigations on '' meta7olism in the human and 7ovine retina demonstrated synthesis o% prostaglandins, including :9E(, :9!( , :9 (, :9D(, >=B. and throm7o;ane '(, as Bell as cycloo;ygenase#lipo;ygenase activities D/3E. '' meta7olites in ocular disease have 7een determined mostly in in%lammatory diseases such as cystoid macular edema. HoBever, some indirect e;periments may indicate a participation o% '' meta7olites in degenerative retinal diseases. Release o% '' ta@es place in the retina under e;perimental conditions including ano;ia and light e;posure, and R:E e;posed to light released >=$. suggesting an involvement in reactive o;ygen intermediate phagocytosis D.)E. >aser irradiation o% the ra77it retina induces alteration in the lipo;ygenase pathBay pointing to a role o% >=B. as a mediator in the chorioretinal in%lammatory reaction D.,E. 'lthough advances have 7een made on the %unction o% '' derivates in the central nervous system, it is yet to 7e determined to Bhat e;tent they participate in 'R8D. $eptides. -yto/ines and -"emo/ines in Early ARMD :eptides, cyto@ines and chemo@ines emerged as important in%lammatory signaling molecules. =hese molecules are produced 7y the nervous system, endocrine organs, plasma, cardiovascular system and immunological cells, and can 7e su7divided into / maFor groups- peptide hormones, neuropeptides and cyto@ines#chemo@ines. Peptide Hormones from Nonneural ources. =his %irst group is e;empli%ied 7y angiotensin, insulin and endothelin and has 7een to date poorly correlated Bith 'R8D. Neurotransmitter and Neuroendocrine Mediators !e.g. Neuropeptides". Aeuropeptides such as su7stance :, calcitonin and neuro@inin ' released %rom sensory neurons contri7ute to the systemic in%lammatory reaction implicated in systemic diseases such as asthma and arthritis. =he peptides su7stance : and calcitonin have 7een reported to participate in the 7lood0retina 7arrier control and in the production o% cyto@ines 7y microglia and astrocytes D.(E. =he neural retina may possess immunomodulatory neuropeptides, although a more detailed investigation into their role in retinal in%lammation is Barranted. Cytokines and Chemokines. $yto@ines and chemo@ines modulate in%lammation %rom initial changes in vascular permea7ility to restoration o% tissue integrity. Cytokines 7ind to in%lammatory cells and induce %ormation o% other cyto@ines and chemo@ines. Some o% the Bell0recogni&ed cyto@ines include interleu@ins, inter%erons, tumor necrosis %actors 2 4 and groBth %actors. Chemokines are smaller than cyto@ines and chemoattractant molecules that control the migration o% leu@ocytes as tra%%ic coordinators in the immune response through 90protein0coupled receptors. $yto@ines and chemo@ines have 7een isolated %rom human tissue in other in%lammatory and degenerative diseases such as 'D and rheumatoid arthritis D./, ..E. =here is recent evidence that cyto@ines and chemo@ines

participate in early 'R8D. n 'R8D proin%lammatory cyto@ines such as interleu@ins , and I and tumor necrosis %actor Bere released %rom the choroid and microglia D.1E. By immunohistochemistry the chemo@ines SD!0,, $$R( and $K$R. as Bell as 8$:0, Bere e;pressed in the neuroretina D.IE. 8$:0, acts as regulator on the turnover o% macrophages and dendritic cells+ in mice that lac@ 8$:0, retinal degeneration has 7een demonstrated D.*E. $K/$R,, Bhich encodes the %ractal@ine 2chemo@ine $K/$>,4 receptor, and its SA:s ?(.3 and =(G)8 are correlated Bith age0related diseases such as atherosclerosis. =he association o% $K/$R, SA: and 'R8D Bas e;amined 7y $K/$R, SA: %reHuencies and protein e;pression on archived sections o% 'R8D and normal eyes. =heir results o% loBered e;pression o% macular $K/$R, may predispose to the development o% 'R8D D.G, .3E. =he accumulation o% chemo@ines and cyto@ines in drusen initiates in%lammatory responses and recruitment o% proangiogenic activated macrophages, there7y stimulating 'R8D progression.

Acute-$"ase Response and Regulatory $roteins in Drusen 'cute0phase response is a reaction occurring in in%lammatory conditions characteri&ed systemically 7y leu@ocytosis, %ever and chemical release o% speci%ic proteins. Some important acute0phase proteins are $R:, ,0antitrypsin, haptoglo7in, ceruloplasmin, %i7rinogen, amyloid and (0macroglo7ulin. $R: and amyloid are part o% the penetra;in class+ they may induce complement activation and activation o% proin%lammatory cyto@ines D1)E. n drusen serum levels o% penetra;in proteins such as $R: have 7een correlated Bith intermediate and advanced 'R8D+ $R: has also 7een implicated as an independent ris@ %actor %or 'R8D D1,E. =he regulatory proteins are multi%unction plasma proteins that 7loc@ the complement cascade 7y 7inding to mem7rane attac@ comple;es and decrease the activity o% $/#$1 convertases D1(E. 'lthough %ormation o% regulatory proteins is normally per%ormed 7y the liver, local retinal e;pression o% these in%lammatory mediators has 7een %ound D(3E. Johnson et al. D/)E demonstrated the presence o% regulatory proteins including mem7rane co%actor protein, and later other proteins including vitronectin and amyloid Bere immunolocali&ed D(GE. =he presence o% regulatory proteins along the drusen sur%ace may represent a compromised R:E phenotype secondary to complement attac@, or a response to local disruption o% a normal relationship o% R:E to drusen D1/E.

-omplement 'ystem Acti&ation =he complement system is a component o% innate immunity Bith a series o% /) interrelated proteins to support phagocytosis o% Baste#invaders. =he system is composed o% / pathBays 2classical, alternative and lectin4, Bhich convert to activate $/ and %orm the mem7rane attac@ comple; 2or $17034. =he %inal mem7rane attac@ comple; releases cyto@ines such as vascular endothelial groBth %actor and platelet0derived groBth %actor. $omplement proteins are a prominent part o% the in%lammatory reaction in other

degenerative diseases such as atherosclerosis. $omplement proteins originate %rom the hepatocytes, Bhile e;trahepatic sources include nervous cells, macrophages and even retinal cells D1.E. n the retinal#choroidal cells the complement proteins $/, $1 and $3 have 7een e;pressed in early 'R8D patients D1)E. 8oreover, complement regulatory proteins such as clusterin, vitronectin, $R, and $D.I have also 7een documented in drusen D(*, 11E. =hese accumulations o% insolu7le deposits on R:E cells 7ecome the target %or anti7ody0mediated complement attac@ stimulation. 8oreover the protein $1a %ound along R:E cells regulated leu@ocyte %unction 7y synthesis o% immune0chemotactic cyto@ines during drusen %ormation D1I, 1*E. 'dditionally, $/ %ragments, the @ey %or human complement cascade activation, are present in drusen D(I, /)E. =he %indings o% complement and associated proteins in drusen provide additional evidence %or in%lammation in early 'R8D 2ta7le ,4.

Immunoglobulin and Immune -omple% mmune comple;es are clusters o% antigens and anti7odies 7ound together %orming a large netBor@ o% molecules. =hese molecules may evolve mainly %rom immunoglo7ulin and complement protein accumulation, resulting o%ten in immune0comple; diseases. Early 'R8D studies revealed the presence o% immunoglo7ulins and maFor histocompati7ility comple; 28H$4 class antigens in su70R:E deposits and drusen D/, /,E. mmunoglo7ulins in drusen 7elong mostly to the g9 su7class, although some anti0 g8 and immunoglo7ulin light0chain have 7een noted. =he presence o% the complement comple;es plus g9 in drusen suggests a process related to immune0comple; %ormation. Besides, the cytoplasmic aggregation o% immunoglo7ulin molecules and $1 complement 7y R:E cells rein%orces the phenomenon o% su7lytic complement0mediated mem7rane attac@ associated Bith immune0comple; patho7iology D1GE 2ta7le ,4.

Inflammatory -ells n%lammatory cells arise %rom 7one marroB stem cells and diverge into ( %amilies. =he myeloid family 2erythrocytes, neutrophils, eosinophils, 7asophils and monocytes#macrophages4. =he microglia are reticuloendothelial mesenchymally derived tissue macrophages+ retinal microglia consist o% macrophages and dendritic cells D13E. =he retinal distri7ution o% microglia %olloBs tBo capillary ple;uses, near hori&ontal and amacrine cells. Human retinal microglia possess immunoreactivity %or many accessory molecules 2$DGI, OK0I4, leu@ocyte mar@ers 2$D.1, $DIG and S(( macrophage antigen+ intercellular adhesion molecule ,4. =he microglia e;press H>'0DR and are activated 7y o;idation and inFury o% R:E#Bruch<s mem7rane in degenerating retinas D(G, (3E. n the su70R:E environment in 'R8D, activated macrophages#microglia possess numerous activities- 2a4 they produce in%lammatory mediators, 274 phagocyte neuroto;ic#small particles as Bide07anded collagens %rom compromised R:E cells destroying the via7le

host tissue and 2c4 they present %oreign antigens to lymphocytes D,), (I, I), I,E. !urther in%lammatory cells involved in su7retinal in%lammation are the giant cells#epithelioid cells attracted 7y the phospholipid accumulation in the su70R:E space. =hey may induce a 7rea@doBn in Bruch<s mem7rane and stimulate 'R8D progression DI)E. 6ith regard to the neutrophils, Bhile they induced e;perimental $A? in a mouse model, there is a lac@ o% in%ormation regarding their importance in early 'R8D DI(E. =he second lymphoid cell line is composed o% B0 and =0cell lymphocytes. B cells undergo terminal di%%erentiation into plasma cells and anti7odies, Bhereas = cells mature into cells Bith sur%ace mar@ers, =. and =G. =he =. helper cells produce lympho@ines to support the multiplication o% B cells. =G cytoto;ic cells @ill cells a%ter %oreign epitope 7inding Bith appropriate 8H$ protein. =he normal porcine retina as a model %or histological study is devoid o% lymphocytes. So %ar no clear identi%ication o% lymphoid cells in drusen or 'R8D has 7een made. 8H$s are protein mar@ers %ound on all cells and the genome segments divided into classes 0 . E;pression o% 8H$ antigens provides the immunological su7strate %or presentation o% e;ogenously and endogenously derived peptides to macrophages and lymphocytes. =he presentation o% antigens 7y retinal microglia demands e;pression o% 8H$ antigens+ such a cyto@ine0induced phenomenon has 7een associated Bith pathological states. :en%old et al. D I/E esta7lished a correlation 7etBeen early 'R8D and an increased 8H$ class immunoreactivity in retinal vascular elements. =he migration and activation o% leu@ocytes into drusen is modulated 7y 8H$ class 7y mo7ili&ation o% the complement system D(,, I,E.

Drusen Deposits Analogous to Age-Related 0eurological and -ardiac Disease Several isolated molecules and proteins lin@ed to drusen have 7een descri7ed in pathological deposits in other organ systems. =he presence o% similar proteins in 'D, glomerular 7asement mem7rane and atherosclerosis supports a hypothesis %or a common pathBay to 'R8D. n atherosclerotic plaHues common molecular constituents to drusen include lipids, vitronectin, apolipoprotein E and complement components DI.E. n atherosclerosis a7normal endothelial cells may e;acer7ate the primary disease %ormation event. Some mediators o% cardiovascular disease have also 7een associated Bit 'R8D DI1E. !eB epidemiological investigations demonstrated that tBo systemic 7iomar@ers %or in%lammation 2$R: and homocysteine4, ris@ %actors %or cardiovascular disease, Bere signi%icantly higher in individuals Bith 'R8D compared to controls D1,E. HoBever, one study e;amined D(339 and =/33 variants o% =oll0li@e receptor . in II* 'R8D patients and ./3 $aucasian controls. =oll0li@e receptors . are candidate genes %or 'R8D suscepti7ility 7ecause o% their chromosome location, a chromosome region e;hi7iting evidence o% lin@age to 'R8D 23H/(0//4 and participating in phagocytosis o% photoreceptor outer segments 7y the R:E. nterestingly, the a7sence o% a correlation o% =oll0li@e receptor . variants and 'R8D suscepti7ility Bas contrary to that o% an association Bith atherosclerosis ris@ DIIE.

$onsecutive studies demonstrated similar molecules and pathBays in neurological diseases and drusen. n neurological diseases such as 'D and :ar@inson<s disease, there is deposition o% 0amyloid plaHues and neuro%i7rillary tangles, Bhich activates the complement pathBays+ investigation on drusen constitution revealed also 0amyloid protein DI*E 2%ig. (4. Other ultrastructural %indings similar to drusen and 'D include cell sur%ace 7le77ing, endocytosis and overe;pression o% modulatory proteins such as clusterin and vitronectin. 8oreover, one @ey event in neurodegenerative disorders such as :ar@inson<s disease and amyotrophic lateral sclerosis similar to drusen is accumulation o% reactive microglia in the degenerative areas DIG, I3E. Recent genetic studies demonstrated an increased ris@ %or 'D and drusen in patients Bith inheritance o% the apolipoprotein E allele. n the 7rain, neural in%lammation enhances apolipoprotein E production, and this protein modulates phospholipid transport %or neural remodeling D*)E. n some 'D cases, high $R: 7lood levels have 7een demonstrated similar to 'R8D, although the e;act cause0e%%ect relationship remains to 7e determined.

Fig 1 !luorescence photomicrograph %rom a postmortem retina o% a patient Bith geographic atrophy. n the area shoBn, golden cells are R:E cells 2auto%luorescent4, overlying a large drusen. =he drusen is immunoreactive %or 0amyloid, as indicated 7y the red %luorescence. =he solid green line is auto%luorescent Bruch<s mem7rane. Auclei are stained 7lue Bith diaminophenylindole. =he scale 7ar represents 1) Lm. $ourtesy o% =&vete Dentchev, 8D, and Joshua >. Dunaie%, 8D, :hD.

Final -onsiderations Mnderstanding the mechanisms o% 'R8D initiation remains a challenge in retina research. 6hile maFor advances have 7een made in recent years, an e%%ort is reHuired %or %urther elucidation o% the @ey pathBays that initiate the sight0threatening disease. Some important areas %or research include the complement system, cyto@ines and microglial cells. $omprehension in the patho7iology o% 'R8D should ena7le novel pharmacological approaches %or the prevention o% 'R8D. Speci%ic anti0in%lammatory drugs may o%%er the opportunity to prevent 'R8D %or elder patients at ris@.

Ac/no2ledgments =he author than@s =&vete Dentchev, 8D, and Joshua >. Dunaie%, 8D, :hD, %or providing %igure ( as a courtesy %or this article.