Oxidative Stress and Cell Membranes in the Pa Tho Genesis of DA

doi:10.1152/physiol.00024.2010 26:54-69, 2011.PhysiologyPaul H. Axelsen, Hiroaki Komatsu and Ian V. J. MurrayPathogenesis of Alzheimer's DiseaseOxidative Stress and Cell Membranes in the

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Oxidative Stress and Cell Membranes inthe Pathogenesis of Alzheimer’s Disease

Amyloid � proteins and oxidative stress are believed to have central roles in

the development of Alzheimer’s disease. Lipid membranes are among the

most vulnerable cellular components to oxidative stress, and membranes in

susceptible regions of the brain are compositionally distinct from those in

other tissues. This review considers the evidence that membranes are either a

source of neurotoxic lipid oxidation products or the target of pathogenic

processes involving amyloid � proteins that cause permeability changes or ion

channel formation. Progress toward a comprehensive theory of Alzheimer’s

disease pathogenesis is discussed in which lipid membranes assume both

roles and promote the conversion of monomeric amyloid � proteins into

fibrils, the pathognomonic histopathological lesion of the disease.

Paul H. Axelsen,1,2 Hiroaki Komatsu,1and Ian V. J. Murray3

Departments of 1Pharmacology, 2Biochemistry and Biophysics,and Medicine, University of Pennsylvania School of Medicine,Philadelphia, Pennsylvania; and 3Department of Neuroscience

and Experimental Therapeutics, Texas A&M Health ScienceCenter, College Station, Texas

The literature of Alzheimer’s disease (AD) researchis vast, complex, and often contradictory. Never-theless, a broad perspective on this literature, andon what typically does and does not happen inbiological systems, suggests either that lipid mem-brane damage is directly involved in the pathogen-esis of AD or that it is an important consequence ofAD. Therefore, investigations into the relationshipbetween membrane damage and amyloidogenesismay yield important insights into AD pathogenesis.

The “amyloid hypothesis” has driven much ofthe research on AD pathogenesis since it was pro-posed in 1991 (123, 124). In its simplest form, thishypothesis suggests that the accumulation of am-yloid beta (A�) proteins in brain tissue drives thepathogenesis of AD. A� proteins originate from alarge transmembrane protein of unknown functionknown as amyloid precursor protein (APP) by theaction of �-secretase and �-secretase activity(FIGURE 1). The specific cleavage site of �-secre-tase is somewhat variable, yielding proteins rang-ing from 39 to 43 residues in length, with 40 and 42residue forms predominating (A�40 and A�42).The non-amyloidogenic pathway for APP process-ing involves �-secretases, a family of enzymes thatcleave APP near the middle of the A� proteinsegment.

The amyloid hypothesis was initially based ongenetic studies of familial AD and the occurrenceof AD-like pathology in Down Syndrome. Amongthe most cited experimental studies in support ofthis hypothesis are those in which A� proteinsimpair physiological and cognitive function wheninjected into rodent brains (72, 136, 184, 282, 320,336). Nevertheless, the amyloid hypothesis hasbeen criticized for being incomplete and vague.

For example, it is unable to explain nonfamilial orsporadic cases of AD (the most prevalent form),how fibril formation leads to neuronal death, thepoor clinicopathological correlation between am-yloid plaque burden and cognitive impairment(279), the hyperphosphorylation and aggregationof tau proteins as neurofibrillary tangles, and ax-onopathies that precede amyloid deposition (302).These criticisms notwithstanding, there are no al-ternative hypotheses with nearly as much support,and the amyloid hypothesis is readily adapted toanswer some of these criticisms. For example, thepathologies that precede amyloid deposition maybe due to prefibrillar intermediate forms of A�

protein, and plaques may represent an inert formof the protein (62, 125, 337). Supporting this idea isthe observation that a variant form of A� that oli-gomerizes but does not fibrillize can nonethelesscause several pathological manifestations of ADother than fibril formation (318).

It has been suggested that there is a tenuousbalance among the rates of A� protein production,aggregation, and elimination in brain tissue, suchthat a small disturbance applied over sufficienttime causes the pathological accumulation of A�

protein as amyloid fibrils in AD. However, the con-centrations of A� proteins in the brain appear to befar lower than their aqueous in vitro solubility (143,238, 281). Therefore, A� proteins should not formamyloid fibrils in the brain even if concentrationsare modestly elevated. Yet, fibrils do form withadvancing age in virtually everyone, indicating thatfactors other than A� protein concentration musthave a role in causing them to form. If smallchanges in protein concentration cannot accountfor fibril formation, then we must consider factors

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such as macromolecular crowding (216, 228),locally high concentrations of A� proteins at syn-apses (71), chemical modification (30, 161, 231,287, 360), cross-linking (17, 22, 290, 291), or metalcomplex formation (6, 31, 92, 105, 153, 272, 284,306). Understanding the chemical mechanismsthat reduce the solubility of A� proteins in braintissue is key to understanding why AD pathologydevelops in some individuals and not others.

Oxidative Stress

Oxidative stress is caused by a dense, complex andheterogeneous network of oxidizing reactions runningcounter to the reducing conditions that otherwise pre-vail in cells and tissues. It has been suggested that theaccumulation of A� proteins in the brain may be aprotective response to oxidative stress (16, 28, 162, 164,273, 292). The density of plaques containing A� proteincorrelates inversely with markers of oxidative damage(75), and the cortical deposition of A� proteinscorrelates with reduced oxidative damage inDown syndrome (236). Moreover, A� proteins pre-vent lipoprotein oxidation (163) and metal-inducedneuronal death in culture (363). However, it is inher-ently difficult to quantify oxidative stress, and attemptsto do this are subject to many methodological pitfalls.For example, a study concluding that the primarymechanism of A� toxicity does not involve oxidativepathways measured thiobarbituric acid reactive sub-stances (TBARS) to assess lipid peroxidation (248).However, assays for TBARS measure only a small sub-set of the diverse oxidation products generated, as wellas substances not derived from lipids. Other studiessuggesting that A� has antioxidant activity were notcontrolled for the inherent redox activity of peptidegroups or conducted in the presence of biologicallyrelevant electron donors and acceptors to drive thereactions (23, 24).

Overall, it seems more likely that A� proteinspromote oxidative stress (42, 50, 91, 201, 202, 254).The brain in AD appears to sustain more oxidativedamage than normal brain (200, 211, 331), exhibitsan increased susceptibility to oxidative stress (190,220, 277), and has relatively low levels of naturallyoccurring antioxidants such as �-tocopherol (144,358). Regions of the brain rich in A� proteins alsohave increased levels of protein oxidation (129).The overexpression of A� proteins in transgenicmice, in C. elegans, and in cell culture, increasesbiomarkers of oxidative stress (256, 345). A� pro-teins cause H2O2 and lipid peroxides to accumu-late in cells (27). Catalase protects cells from A�

toxicity, and cell lines selected for resistance to A�

toxicity also become resistant to the cytotoxic ac-tion of H2O2. A� proteins promote the oxidation ofcompounds such as dopamine, phospholipids, andcholesterol (40, 134, 135, 235, 241, 257, 356) as long

as an intact methionine side chain is present (5, 21,45, 47, 49, 232).

A� proteins and amyloid plaques bind redox-active transition metals that are likely to be theactual site of redox activity (76, 273). Copper levelsare significantly increased in amyloid plaques (183,191, 304), although comparatively subtle increasesin copper transport across cell membranes maycause significant changes in A� protein turnover(321). Excess dietary copper increases AD-like pa-thology in a mouse model (160). Cu2� and Zn2�

chelators appear to inhibit A� deposition in thebrains of mouse models (64), and metal depletionpromotes the disaggregation of A� fibrils (65).Cu2� potentiates the neurotoxicity of A�42 � A�40in embryonic rodent neurons, and its effect is me-diated by H2O2 (135, 355). Studies of copper in thepathogenesis of AD have been extensively reviewed(39, 90, 100, 305). In contrast, Zn2� ions are redox-inert and able to protect/rescue human cells intissue culture from A� and Cu2� toxicity (75). Arecent study, however, observed that the zinc re-leased at synapses with neurotransmitters causedthe accumulation of toxic A� oligomers to thesemembranes (86).

It has been suggested that A� proteins split intofragments that are both neurotoxic and able togenerate additional oxygen radicals (48, 128), al-though these findings have been strongly refuted(89). Nevertheless, electron paramagnetic reso-nance spectroscopy has shown that there is astrong correlation between the intensity of radicalgeneration by A� and neurotoxicity (219). In thesestudies, preincubation of A� to form fibrils in-creased its toxicity. In contrast, replacing the re-dox-active sulfur atom in residue Met35 withmethylene (CH2) resulted in a peptide that formedfibrillar structures but had no demonstrable toxic-ity toward cultured hippocampal neurons. In thesame experimental system, vitamin E (presumablyacting as an antioxidant) neutralized the neurotox-icity of A� but had no effect on its ability to form

FIGURE 1. Processing of the amyloid precursor proteinA� proteins are 39- to 43-residue segments within the 770-residue amyloid precursorprotein (APP), beginning at residue 672. The non-amyloidogenic processing pathway iscatalyzed by �-secretase, which cleaves in the midst of the A� protein segment. Theamyloidogenic pathway is catalyzed by �-secretase, which cleaves an extracellular site ofAPP, and �-secretase, which cleaves at points within the transmembrane segment.

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fibrils (332). Another study concluding that freeradicals do not mediate A�-induced neurotoxicityused ginkgolides (a purported anti-oxidant compo-nent of Ginkgo biloba leaves) and vitamin E toinhibit oxidation (351). Although neither agentprotected cells from apoptosis and death, it is un-likely that they completely halted radical-mediatedoxidative damage.

Proteomics studies of oxidative stress have fo-cused on proteins damaged by oxidation, nitration,and other reactive substances (41, 44, 50, 51, 57, 58,60, 80, 107, 243, 285, 293, 317). In most cases,reactions with protein carbonyl groups are takenfor evidence of damage by oxidation, and the na-ture of the protein modification is not explicitlydefined. Two studies have examined the ability ofA� proteins to induce oxidative modifications inother proteins (34), and A� proteins may also un-dergo oxidative damage, particularly His, Tyr, andMet side chains (15, 32, 43, 132, 139). However, it isdifficult to imagine how oxidative damage to pro-teins, especially A� proteins, would lower theaqueous solubility of A� proteins and promote fi-bril formation.

Enter Lipid Membranes

Investigations into the role of lipids in AD are ex-perimentally challenging because they are chemi-cally diverse, with thousands of distinct molecularspecies present in every cell. They are also physi-cally diverse, rarely existing as monomeric speciesin solution unless protein bound. In vitro, the vastmajority form micelles or vesicles, and the lattermay be unilamellar or multilamellar. Thus lipidsuspensions generally have two or more phasesand complex interphase equilibria. This physicalheterogeneity complicates most types of physico-chemical analysis, even when pure synthetic lipidpreparations are used, and it makes some othersoutright impossible. It also impedes the measure-ment of fibril formation. Turbidity measurements,for example, are confounded by ambiguity overwhether the species causing the turbidity is proteinor lipid. Lipids markedly increase the fluorescenceof the thioflavin T apart from fibril formation,whereas assays based on Congo Red absorbanceratios entail practical restrictions on protein andlipid concentrations that limit the flexibility of thisassay. The presence of membranes can also com-plicate sample preparation, and they yield artifactswhen the halogenated solvents used to disaggre-gate A� proteins are not completely removed (56,310).

Due in part to these challenges, the evidencethat cell membranes are involved in the pathogen-esis of AD remains largely circumstantial, eventhough the amount of evidence pointing to some

type of link is overwhelming. A� proteins are pro-duced by cleavage of APP at two sites, one sitebeing located approximately at the midpoint of thetransmembrane segment (FIGURE 1). As a conse-quence, the COOH-terminal residues of A� pro-teins that were part of the APP transmembranesegment are uniformly hydrophobic. Followingtheir cleavage from APP, some investigators haveobserved that A� proteins remain associated withdetergent-resistant lipid membrane domains inthe brain (181), or with membrane-anchored APP(189). It has also been hypothesized that A� pro-teins bind to the transmembrane helices of mem-brane proteins and cause their dysfunction (199).Ultrastructural studies suggest that amyloid fibrilformation tends to occur first in portions of diffuseamyloid deposits that are closest to membranes(234, 319, 346). A�40 with the E22Q mutation (re-sponsible for hereditary cerebral hemorrhage withamyloidosis-Dutch type) will fibrillize on the sur-face membrane of human cerebrovascular smoothmuscle cells (330).

Despite a substantial hydrophobic segment, thegeneral conclusion reached by most investigatorsis that A� proteins have little affinity for neutrallipid membranes (205). Techniques such as thehydration of a mixed protein-lipid film must beused to induce the penetration of A� proteins intoa neutral lipid bilayer (83). One laboratory investi-gating A�40 and another investigating A�42 havedocumented that the proteins situate differently inmembranes depending on whether they are em-bedded in a bilayer membrane or allowed to asso-ciate with the surface of a preformed membrane(33, 106, 176). In general, anionic lipids tend toinduce A� proteins to adopt extended � structure(35, 63, 66, 76, 130, 167–169, 204, 213, 214, 313, 314,344, 352). Possible reasons for the inducement of �

structure and fibril formation by protein-lipid in-teraction have been reviewed, including the abilityof such interactions to serve as templates for struc-tural change, to increase the local concentration ofprotein, and to orient protein monomers relative toeach other (2, 113). A� proteins adopt �-helicalstructure in association with lipid membranes atlow lipid-to-protein ratios (315), at high cholesterolconcentrations (145), or in conjunction with metalions (21, 76, 77). Some investigators have found thatdetergent micelles promote �-helical structure (283),whereas others find that it promotes the formation ofoligomers with � structure (261). Spontaneous inser-tion into various membranes has been observed forA� segments (82) and for A� proteins at relatively lowmembrane surface pressures (94).

The relative abundance of various lipid classes inmembranes is altered in AD (121, 227, 247, 252,350), and altering membrane composition protectsPC12 cells from toxic effects of A� proteins (338).

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Altered physical properties, presumably arisingfrom compositional differences, have been ob-served in hippocampal membranes of AD brains(364). Plasmalogen deficiency is frequently associ-ated with AD (102, 110 –112, 119, 120, 229). In ad-dition to having an effect on membrane physicalproperties, plasmalogens are particularly suscepti-ble to oxidative damage (156 –158). This suscepti-bility may confer on plasmalogens the ability toprotect other lipid species by diverting and trap-ping oxidizing agents (36, 117, 118, 170, 195, 196,222, 230, 242, 264, 362). Cerebral white matter isenriched in plasmalogens for unknown reasons(101).

Human epidemiological studies support a linkbetween AD and the consumption of �-3 polyun-saturated fatty acyl (PUFA) chains (103, 141, 223,224, 237, 250, 275, 323), and this association issupported by animal model and cell culture stud-ies (53–55, 126, 146, 185, 193, 350). The most prev-alent �-3 PUFA in the brain is docosahexaenoicacid (DHA), and dietary DHA supplementation al-leviates both AD-like histopathology and cognitiveimpairment in animal models (53, 55, 126, 185).The metabolism of DHA in normal brain is remark-able in several respects (159), and it is difficult toinduce a measurable deficiency of DHA-containinglipids in the brain tissue of animal models throughdietary restriction (84). Animal studies have shownthat the brain responds to a dietary deficiency ofDHA by elongating arachidonic acid (ARA) chains.Because there are no enzymes capable of desatu-rating the distal end of these PUFA chains, theresult is a marked increase in docosapentaenoicacid (DPA) chains (138).

A� proteins appear to have special relationshipsor interactions with specific lipid species. For ex-ample, the ganglioside GM1 is bound together withA� proteins in diffuse amyloid plaques (348). GM1-containing membranes promote the formation of� structure (212, 215), � structure (206), or fibrils invitro (67– 69, 115, 127, 148 –151, 165, 207, 218, 239,240, 334, 335). In several of these reports, GM1 ispresented in raft-like membrane subdomains inwhich cholesterol is a significant component, andrafts have also been discussed as an influence onthe processing of APP into A� proteins (74). Apartfrom rafts, cholesterol has been epidemiologically(289, 311) and experimentally (263, 300) linked tothe incidence of AD, and it may influence the pro-duction (108, 361), location (77, 87, 145), behavior(79, 214, 352), or toxicity (38, 78, 137, 308, 338) ofA� proteins. In models of Niemann-Pick Type Cdisease, A� proteins accumulate along with cho-lesterol (347).

Cholesterol depletion reduced the �-cleavage ofAPP and the production of A� proteins in a study ofneurons in the rat hippocampus (288). Treatment

with lovastatin/mevalonate alone, however, was in-sufficient to induce a significant effect; treatmentwith �-cyclodextrin to achieve a 70% reduction ofcellular cholesterol content was also required. It hasbeen suggested that the dependence of A� proteinproduction on cholesterol is due to the selective ac-tivity of �-secretase activity in cholesterol-dependentraft-like subdomains of the plasma membrane,whereas �-secretase activity appears to predominatein non-raft domains (95). Some �-secretase stimula-tion has also been attributed to neutral glycosphin-golipids and anionic phospholipids (152). Theefficacy of a �-secretase inhibitor has been increasedby linking it to cholesterol and thereby targeting it tomembranes (260).

The Membrane as Villain

The lipids in cell membranes are often regarded asbeing chemically unreactive and merely a physicalbarrier or a support matrix for proteins. That viewis misleading on many levels, of course, but par-ticularly so when the membrane lipids containPUFA chains and are subjected to oxidative stress.Reviews of the role of membranes in AD pathogen-esis frequently overlook the effects of oxidativestress and chemical modification of PUFA chainson membrane properties. A� proteins have aprooxidant activity toward polyunsaturated lipidsthat can be neutralized by lipophilic antioxidants,chelation of metal ions, anaerobic conditions, mu-tation of His13 or His14 to Ala, or modification ofthe Met35 side chain (232). Lipid oxidation prod-ucts and the susceptibility of lipids to oxidativedamage are both increased in AD (78, 104, 210,309). Several reports have outlined the potential fora complex interplay between cholesterol oxidationproducts and A� proteins (38, 116, 235, 241, 301,329, 356, 360).

The myriad mechanisms of oxidative stress yielddiverse chemically reactive products from PUFAchains including hydroxy- and hydroperoxy-lipidsthat undergo spontaneous decomposition, lipidfree radicals that may participate in free-radicalchain reactions, as well as fragments such as ma-londialdehyde, acrolein, and hydroxynonenal withthe potential to form adducts with proteins andnucleic acids (61, 270, 274, 293, 295, 296). Thesematerials are direct toxic threats to the tissues inwhich they are generated. Brain is the most lipid-rich organ in the body, and it contains more lipidsbearing PUFA chains than any other organ. There-fore, brain tissue is at particularly high risk forchemical injury due to highly reactive lipid oxida-tion products.

Evidence that lipid peroxidation may be involvedin the pathogenesis of AD has been extensivelyreviewed (13, 42, 46, 201). Lipid hydroperoxides

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undergo spontaneous (nonenzymatic) decomposi-tion, and �-6 PUFA chains yield reactive �,�-un-saturated aldehydes such as 4-oxo-2(E)-nonenal(180) and 4-hydroxy-2(E)-nonenal (HNE) (97, 98),as well as eicosanoids such as isoprostanes (225,226). The prooxidant activity of A� proteins men-tioned above can catalyze the formation of HNEfrom �-6 PUFAs in the presence of copper ions(232). Isoprostanes are relatively unreactive com-pounds that have been used as biomarkers of oxi-dative stress (179, 221, 244, 268). Some reportssuggest that isoprostanes are specifically elevatedin AD (253, 255, 256), although these findings havenot been confirmed by all investigators (221, 357).Analogous products derived from �-3 PUFA chainshave been dubbed “neuroprostanes” and also havebeen put forward as indexes of oxidative stress inthe brain (14, 266, 267, 298).

Compared with isoprostanes, HNE is chemicallyreactive, with a well known propensity to formadducts with the side chains of various amino acidresidues (37, 98, 328). For this reason, HNE-proteinadducts have also been used as biomarkers of ox-idative stress (325). HNE concentrations in humanventricular fluid are �15 �M and are elevated inAD (190, 203, 210). HNE modification is also knownto inhibit proteasome function (286) and gluta-mate transport in synaptosomes (177). Togetherwith the observation that immunoreactivity of an-tibodies to HNE-modified His residues localizes toamyloid plaques (7, 294), these observations sug-gest that A� proteins not only promote lipid oxi-dation but that there may also be a mechanisticlink between the lipid oxidation products formedduring oxidative stress and A� misfolding (161).

A� proteins increase HNE production from PUFAchains in vitro that, in turn, causes covalent modifi-cation of the three His residues in A� proteins andfibril formation (231). These modifications promotethe aggregation of A� proteins into fibrils (FIGURE 2)(165, 231, 232). Moreover, they increase the ability ofA�42 to seed fibril formation by unmodified A�40(166). The effects of HNE on A� fibril formation de-pend on the size or hydrophobicity of the modifica-tion because the corresponding analog from �-3PUFA chains, 4-hydroxy-2(E)-hexenal, does not havethis effect (187). The addition of an octanoyl group tospecific Lys residues of A� proteins also appears tohave a pro-amyloidogenic effect (258).

In vivo, HNE-His epitopes are concentrated inthe vicinity of amyloid plaques, but they do notprecisely co-localize with the plaques (FIGURE 3).One possible explanation for this distribution isthat the presence of HNE-His adducts and Cu-Hiscomplexes in the same protein molecule are mu-tually exclusive. Presumably, the formation of Cu-His complexes precedes the generation of HNEand HNE-His adducts, if indeed they are responsi-

ble for generating HNE from �-6 PUFAs. Conse-quently, HNE-His epitopes would develop aroundpreexisting amyloid plaques, not within them. Asecond possibility is that A�-specific antibodyepitopes are masked by HNE modification, as ob-served in vitro for 4G8 and 6E10 epitopes (231). Athird possibility is that A� fibrils induced to formby HNE modification have relatively sparse HNE-His epitopes (as suggested by FIGURE 2), yieldingsparse fluorescence among fibrils. The fluores-cence of HNE-11S seen in FIGURE 3 may be toHNE produced in the plaque but bound to HNE-His adducts in proteins other than A� proteins.

Some investigators have focused on the role ofacrolein in the pathogenesis of AD. Acrolein is a wellknown environmental toxin and a recently recog-nized product of lipid peroxidation (324, 326, 327). Itreacts spontaneously with Lys residue side chains,forming a cyclic Nε-(3-formyl-3,4-dehydropiper-idino) derivative that has been considered abiomarker for measuring oxidative stress in AD(52). Acrolein is elevated in AD brain, it appearsto be more neurotoxic than HNE, it causes ele-vated intracellular calcium levels (192, 342), andit appears to inactivate flippase, inducing abreakdown of lipid membrane asymmetry andapoptosis (1, 59).

The Membrane as Victim

Although the foregoing discussion suggests that ADmay be caused by membrane-derived neurotoxicagents, a contrasting view is that AD is due to

FIGURE 2. Electron micrograph of fibrils inducedby HNE modificationA�42 was induced to fibrillize with HNE, then treatedwith mouse anti-His-HNE, and gold-tagged anti-mouseantibody. The focus in this image is on the gold parti-cles, but various fibril morphologies are evident, and thegold particles making anti-HNE-His antibodies are pref-erentially associated with long, relatively straight fibils.

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physical attacks on the barrier function of mem-branes (265). For example, A� proteins or theirfragments have been observed to penetrate themembrane surface (82, 94), disrupt raft-like do-mains (67), cross the membrane (341), induce iso-tropic phases (176), increase the permeability ofmembranes to various materials (154, 344), causephysical thinning (81), decrease the mobility ofhydrophobic membrane probes (169), activatephospholipase A2 (182), and promote membranefusion (81, 249). Membrane binding by A� proteinsappears to mediate some forms of neurotoxicity(21, 70, 316). Plasma membranes isolated from hu-man brain accelerate A� fibrillogenesis (339),whereas fibrillizing A� proteins disrupt the struc-ture of membranes formed from both syntheticlipids (168, 169) and whole-brain lipid extracts(353). The action of A� proteins on membranes hasbeen compared with the action of antimicrobialpeptides, and homogenates of brain with AD haveelevated antimicrobial activity (299). Among theeffects of A� proteins on membranes, however, theformation of ion channels has received the mostattention (10 –12, 93, 147, 186, 251).

A� proteins share an ability to induce channel-likeactivity in membranes with a wide variety of otheramyloid-forming proteins (259). In the case of A�, thechannels exhibit only modest cation selectivity butvery long lifetimes. A� cation channels can beblocked by Zn2�, suggesting the possibility that theymay be therapeutic targets (9), and small moleculeinhibitors of the A� calcium channel have been de-scribed (88). Ring-like structures possibly represent-ing these pores or channels have been observed inmembranes by AFM (173, 186, 259) and EM (174,175). Although such features are not always observedwith A� proteins (114, 341), there are many reportssuggesting that they are formed by other amyloido-genic proteins such as the insulin-associated poly-peptide, �-synuclein, and serum amyloid A protein(259). It has been suggested that the channel-forming

toxic properties of A� proteins on a membrane de-pends on the extent to which it has aggregated intooligomers and that this extent is concentration de-pendent (276). Model structures of the purportedchannels have been patterned after �-barrel pore-forming toxins (8, 93). This comparison is suggestednot only by the EM/AFM images but by the reactivityof A� and �-hemolysin with so-called “conforma-tion-specific” antibodies (354). Recent studies con-firming the formation of zinc-sensitive ion channelshave also exposed the potential for artifact due toresidual amounts of halogenated solvent in the A�

protein samples (56).It may be significant that truncated A� peptides

that are unable to form fibrils can neverthelessinduce ion permeability (142) and that membranesformed from highly compressible lipids are mostsensitive to A�-induced changes in permeability(297). It has been suggested that channel openingsare merely protein-induced defects in the bilayerstructure or organization that heal after a time,giving the appearance of a transient channel open-ing (114). This mechanism would be consistentwith oligomer-induced membrane thinning (297)and would help resolve the paradoxical appear-ance of many simultaneous pore structures inmembranes that exhibit only single channel con-ductances (96).

In living cells, as opposed to synthetic systems,one must consider the possibility that A� may pro-foundly affect the behavior of naturally occurringchannels and transporters. For example, A�42 in-creases HNE-modification of a glutamate trans-porter in synaptosomes (177). A� oligomers havebeen implicated in causing a pathological calciuminflux through hippocampal NMDA receptors, fol-lowed by the activation of calpain and the degra-dation of dynamic 1-a GTPase involved in synapticvesicle recycling (155). A� proteins have also beenshown to depress the surface concentration ofAMPA receptors involved in calcium regulation at

FIGURE 3. Immunofluorescent staining of the posterior parietal association area in a transgenic mouse model of Alzheimer’sdisease that expressed amyloid precursor protein with the “Swedish” K670N/M671L mutation, and presenilin 1 with theM146L mutationA: 2H4 antibodies (Covance) specific for the amino terminus A� proteins (green). B: HNE 11S specific for HNE-His adducts (red). C: A and Bsuperimposed. Possible reasons for the close association of HNE-His epitopes and A� proteins, but not precise colocalization, are discussedin the text.

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the synapse (133, 188). The dysregulation of cal-cium has long been associated with AD pathogen-esis (172) and is thought to be involved with theaccumulation of amyloid deposits (85, 208, 209)and the hyperphosphorylation of tau (25). Calciumalso promotes the conversion of oligomeric A� tofibrils (140). An extensive literature exists on therole of mitochondria in AD pathogenesis, and theaccumulation of calcium by mitochondria fol-lowed by damage to the mitochondrial membranestructure is a prominent theme in this literature(131, 246, 262).

The Lipids Associated WithApolipoprotein E

The lipids in nascent lipoprotein particles are ar-ranged in a membrane-like bilayer, surrounded byapolipoprotein molecules in a configuration oftencalled the “belt” model (FIGURE 4) (280). Apolipo-protein E (ApoE) is a focus of considerable interestbecause its isoforms are strongly associated withthe risk of developing AD. In plasma, ApoE is foundwith other proteins in lipoprotein particles as di-verse as chylomicrons and high-density lipopro-teins. In the brain and cerebrospinal fluid, ApoE isthe most abundant apolipoprotein and is found inparticles that resemble high-density lipoproteinsin both density and size (269). Among the threecommon isoforms, ApoE3 is the most common(77% of the alleles) and is therefore considered tobe the wild type. ApoE2 has an R158C substitution,whereas ApoE4 has a C112R substitution, and bothare associated with forms of hyperlipidemia (197).One copy of the ApoE4 gene confers a threefoldincreased risk of Alzheimer’s disease, whereas two

copies confer an eightfold increased risk. One copyof the ApoE2 gene, however, reduces the risk by60% (73).

In addition to the epidemiological evidence,there is an abundance of experimental evidencelinking ApoE to the pathogenesis of Alzheimer’sdisease. For example, the ApoE4 allele is associatedwith increased A� deposits in the brain, anda distinct neuropathological phenotype (278),whereas a lack of ApoE reduces A� deposition inmice (19). Amyloid plaques bind anti-ApoE anti-bodies, suggesting that ApoE is present in theseplaques (3). Indeed, ApoE copurifies with A� fromamyloid plaques (26) and may exist as a boundcomplex with A� proteins (245, 349). Some havesuggested that ApoE4 accelerates fibril formationby A�40 (18, 194, 271, 343), but its behavior in thisregard may depend on whether it is monomeric ordimeric. Others have suggested that dimeric formsinhibit fibril formation and that ApoE3 is muchmore effective at doing this because a large fractioncirculates as a disulfide-linked dimer, whereasApoE4 cannot form disulfide bonded dimers due toits C112R substitution (99, 340). Despite all of theseobservations, the reason that different isoforms ofApoE have different levels of risk for AD is not known.There are no isoform-dependent differences in theapparent structure of lipoprotein particles (280). Acase for isoform-specific direct interactions betweenApoE and A� proteins has been made (233), but clearconclusions are elusive due to problems with proteinpurity, aggregation and denaturation of the ApoEprotein, and indirect assay methods (4, 171, 198, 245,303, 307).

Others have suggested that risk of AD with ApoEisoforms may be related to differences in antioxi-dant activity (178, 217, 312). ApoE4 has no Cysresidues and, hence, no free thiol groups; ApoE3has one Cys, whereas ApoE2 has two. Free thiolgroups have significant antioxidant activity viamechanisms that differ from those of glutathione(109, 333, 359). In apoA-I, variants with a free Cysresidue side chain exhibit significantly greater an-tioxidant activity than variants without a free Cysresidue (29). Therefore, it is intriguing to speculatethat ApoE4 confers increased risk of AD, whereasApoE2 confers decreased risk, because Cys residueside chains protect lipids in lipoprotein E particlesagainst oxidative stress.

Toward a Comprehensive Theoryof AD Pathogenesis

The cause of AD is known in cases of familialdisease, but that knowledge has not clarified howsporadic disease develops, nor has it so far yieldedan effective therapy for either form of the disease.Clearly, we need a more detailed theory of AD

FIGURE 4. Nascent lipoprotein E particles consist of�-helical “belts” around the perimeter of a lipid bilayerdiskFor this arrangement and the number of protein and lipid mole-cules in a particle, there is excess protein, which may situateacross the face of the disk. When the protein is apoE3, there isone thiol group for every 45 lipids, concentrating a large antioxi-dant capacity in close proximity to the lipids.

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pathogenesis, and it seems likely that lipid mem-branes will have a prominent role in any suchtheory. As summarized above, the interactions be-tween lipid membranes and A� proteins are bi-directional: lipids damage A� proteins, and A�

proteins damage lipid membranes. These pro-cesses can operate in tandem to accelerate fibrilformation in human brain lipid extracts (231). Evenif fibril formation is only an inert by-product of thedisease-causing process, it is nonetheless a patho-gnomonic finding of AD. Therefore, it is vital tounderstand how fibrils form.

As illustrated in FIGURE 5, the interaction of lipidmembranes may constitute an amplification sys-tem for fibril formation. A� proteins in vitro onlyform fibrils at micromolar concentrations and afterdays of incubation, whereas membranes contain-ing PUFA-chains lower the protein concentrationrequirement by three orders of magnitude andshorten the time required to minutes (165, 166).The same system may also amplify multiple mech-anisms of neurotoxicity that operate indepen-dently of fibril formation and link many of theseemingly unrelated observations reviewed above.For example, inflammation due to trauma or otherfactors will promote oxidative stress and the pro-duction of reactive oxygen species that exert directneurotoxicity or lipid damage and A� protein ag-gregation. Lipid oxidation products may exertdirect toxicity. ApoE4 proteins are deficient inthiol-mediated antioxidant activity; this deficiencywould allow excess oxidative damage to the lipidsin lipoprotein particles that likewise promote A�

protein aggregation. Aging is associated with re-duced tissue antioxidant levels, accumulated oxi-dative lipid damage, and low levels of adventitialA� protein aggregation, with each process promot-ing further A� protein aggregation. Various aggre-gated forms of A� protein may form pores,channels, or other neurotoxic structures in neuro-nal membranes.

It is not yet clear whether all cases of AD arisethrough the operation of one primary pathogenicmechanism that diverges only at a late stage intovarious subtypes or whether disparate mecha-nisms operate from the beginning. For example,neurofibrillary tangles of tau protein (20, 322) oc-cur in only 70 – 80% of cases of AD (122), suggestingthat tangles reflect a response to some but not allpathogenic paths. In any case, one or more addi-tional factors must be incorporated into the amy-loid hypothesis to explain the pathogenesis of AD,and confronting the experimental challenges pre-sented by lipids and membranes may be necessaryto identify such factors. �

No conflicts of interest, financial or otherwise, are de-clared by the author(s).

The authors are supported by grants from the NationalInstitute on Aging, the Alzheimer’s Association, and theAmerican Health Assistance Foundation.

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FIGURE 5. Membrane-mediated amplification of fibrillogenesis, illustratingpossible relationships between meachanisms involved in A� proteinaggregation and neurotoxic mechanisms involved in the pathogenesis ofAlzheimer’s diseaseLipid oxidation products modify the three His residues of A�42, increasing its membraneaffinity and accelerating the conversion of A�40 into oligomers and fibrils. Oligomeric A�proteins bind copper ions while they undergo redox cycling. Highly reactive oxygen spe-cies may be generated by electrons from copper or as by-products of inflammation, in-cluding inflammation induced by trauma. ApoE4 alleles lack thiol-mediated antioxidantactivity and may allow excess oxidative damage to the lipids in lipoprotein particles. Agingby itself is associated with reduced tissue antioxidant levels and accumulated oxidativelipid damage. During any or all of these processes, direct neurotoxins may be produced,and A� proteins may form pores, channels, or other disruptive neurotoxic structures inneuronal membranes.

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