Amyloid β-Protein Toxicity and the Pathogenesis of Alzheimer Disease (2008)

Although amyloid deposition was noted by Alzheimer in 1907 (1Alzheimer A. Stelzmann R.A. Schnitzlein H.N. Murtagh F.R. Clin. Anat. 1995; 8: 429-431Crossref PubMed Scopus (775) Google Scholar), it has been only 17 years since the toxicity of Aβ 2The abbreviations used are: Aβ, amyloid β-protein; AD, Alzheimer disease; APP, amyloid precursor protein; NFTs, neurofibrillary tangles; FAD, familial AD; ADDLs, Aβ-derived diffusible ligands; LTD, long-term depression; MAPK, mitogen-activated protein kinase; NMDA, N-methyl-d-aspartate; GABA, γ-aminobutyric acid. was first described (2Yankner B.A. Duffy L.K. Kirschner D.A. Science. 1990; 250: 279-282Crossref PubMed Scopus (1917) Google Scholar). The prevailing view through most of the twentieth century was that Aβ is a marker of disease progression in AD but does not play a role in the neurodegenerative process. This view changed in the 1990s with the articulation of the amyloid hypothesis, which posits that abnormal accumulation of Aβ in the brain is a direct cause of neurodegeneration and cognitive decline in AD. The hypothesis is supported by the identification of mutations in APP (3Goate A. Chartier-Harlin M.C. Mullan M. Brown J. Crawford F. Fidani L. Giuffra L. Haynes A. Irving N. James L. Mant R. Newton P. Rooke K. Roques P. Talbot C. Nature. 1991; 349: 704-706Crossref PubMed Scopus (3811) Google Scholar) and presenilins 1 and 2 (4Sherrington R. Rogaev E.I. Liang Y. Rogaeva E.A. Levesque G. Ikeda M. Chi H. Lin C. Li G. Holman K. Tsuda T. Mar L. Foncin J.-F. Bruni A.C. Montesi M.P. Nature. 1995; 375: 754-760Crossref PubMed Scopus (3599) Google Scholar, 5Levy-Lahad E. Wasco W. Poorkaj P. Romano D.M. Oshima J. Pettingell W.H. Yu C.E. Jondro P.D. Schmidt S.D. Wang K. Crowley A.C. Fu Y.-H. Guenette S.Y. Galas D. Nemens E. 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Nature. 1966; 209: 109-110Crossref PubMed Scopus (224) Google Scholar) suggested that plaque numbers were directly related to quantitative measures of cognitive decline in the aged population. However, subsequent studies carried out by Terry et al. (10Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. Ann. Neurol. 1991; 30: 572-580Crossref PubMed Scopus (3423) Google Scholar) cast doubt on the predictive value of plaque numbers, suggesting instead that NFTs and synapse loss were more reliable predictors of cognitive decline. Moreover, plaque formation is a common feature of the aging human brain that can occur in the absence of cognitive decline (11Yankner B.A. Lu T. Loerch P. Annu. Rev. Pathol. 2008; 3: 41-66Crossref PubMed Scopus (473) Google Scholar). More recently, it has been suggested that accumulation of toxic oligomers of Aβ may be more relevant than plaques to mechanisms involved in cognitive decline. Transgenic mouse models expressing APP and presenilin variants associated with FAD have provided important insights into structural, neurophysiological, and behavioral effects of Aβ accumulation in the brain (12Morrissette D.A. Parachikova A. Green K.N. LaFerla F.M. J. Biol. Chem. 2009; 284 (in press)Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). Multiphoton imaging studies have demonstrated disrupted neurites and decreased spine density in association with fibrillar Aβ deposits in the Tg2576 transgenic mouse model that expresses the APPsw mutation (13Knowles R.B. Wyart C. Buldyrev S.V. Cruz L. Urbanc B. Hasselmo M.E. Stanley H.E. Hyman B.T. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 5274-5279Crossref PubMed Scopus (206) Google Scholar, 14Spires T.L. Meyer-Luehmann M. Stern E.A. McLean P.J. Skoch J. Nguyen P.T. Bacskai B.J. Hyman B.T. J. Neurosci. 2005; 25: 7278-7287Crossref PubMed Scopus (477) Google Scholar). In addition, stereologic mapping of neuronal cell density showed some degree of neuronal loss in the immediate vicinity of Aβ deposits (15Urbanc B. Cruz L. Le R. Sanders J. Ashe K.H. Duff K. Stanley H.E. Irizarry M.C. Hyman B.T. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 13990-13995Crossref PubMed Scopus (188) Google Scholar). The neuritic dystrophy observed in APP transgenic mice appears to be directly related to the fibrillar component of Aβ deposits. When the APP transgenic was placed on an apoE-deficient background, Aβ deposition still occurred, but fibrillar deposits were absent, and neuritic dystrophy was markedly reduced. When apoE3 or apoE4 was expressed, fibrillar Aβ deposits appeared with concomitant neuritic degeneration that was greater for apoE4 than for apoE3 (16Holtzman D.M. Bales K.R. Tenkova T. Fagan A.M. Parsadanian M. Sartorius L.J. Mackey B. Olney J. McKeel D. Wozniak D. Paul S.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 2892-2897Crossref PubMed Scopus (733) Google Scholar, 17Holtzman D.M. Fagan A.M. Mackey B. Tenkova T. Sartorius L. Paul S.M. Bales K. Ashe K.H. Irizarry M.C. Hyman B.T. Ann. Neurol. 2000; 47: 739-747Crossref PubMed Scopus (268) Google Scholar). However, it was unclear from these studies which came first, neuritic degeneration or deposition of fibrillar Aβ. Another study suggested that axonal dystrophy and altered axonal transport occur early in AD and may lead to amyloid deposition (18Stokin G.B. Lillo C. Falzone T.L. Brusch R.G. Rockenstein E. Mount S.L. Raman R. Davies P. Masliah E. Williams D.S. Goldstein L.S. Science. 2005; 307: 1282-1288Crossref PubMed Scopus (981) Google Scholar). The question of which comes first, amyloid or neuritic dystrophy, was recently addressed by in vivo multiphoton microscopy in an APPswe/PS1d9XYFP transgenic mouse in which the onset of plaque formation could be accurately dated. Plaque formation was followed by progressive neuritic abnormalities that appeared in direct contiguity to the plaque, establishing a causal relationship between amyloid deposition and neuritic dystrophy (19Meyer-Luehmann M. Spires-Jones T.L. Prada C. Garcia-Alloza M. de Calignon A. Rozkalne A. Koenigsknecht-Talboo J. Holtzman D.M. Bacskai B.J. Hyman B.T. Nature. 2008; 451: 720-724Crossref PubMed Scopus (818) Google Scholar). In addition, plaques could form quickly, within 24 h, suggesting that amyloid deposition is a more dynamic process than previously appreciated. Although these findings suggest that neuritic dystrophy can be induced by fibrillar Aβ deposition, it remains to be determined whether this is mediated by Aβ fibrils or by oligomeric intermediates associated with fibrils (20Chimon S. Shaibat M.A. Jones C.R. Calero D.C. Aizezi B. Ishii Y. Nat. Struct. Mol. Biol. 2007; 14: 1157-1164Crossref PubMed Scopus (464) Google Scholar). A limitation of APP transgenic mouse models is the paucity of neuronal cell death and tau-related pathology characteristic of human AD (21Games D. Adams D. Alessandrini R. Barbour R. Berthelette P. Blackwell C. Carr T. Clemens J. Donaldson T. Gillespie F. et al.Nature. 1995; 373: 523-527Crossref PubMed Scopus (2251) Google Scholar, 22Irizarry M.C. Soriano F. McNamara M. Page K.J. Schenk D. Games D. Hyman B.T. J. Neurosci. 1997; 17: 7053-7059Crossref PubMed Google Scholar). Two potential explanations have been posited: either Aβ is not sufficient to account for the neurodegenerative process in AD, or rodent models do not accurately recapitulate the aging human brain. Evidence for the latter explanation comes from the introduction of plaque-equivalent concentrations of pre-fibrillized Aβ into the brains of aging rhesus monkeys, which induced neuronal cell death, tau pathology, and microglial activation (23Geula C. Wu C.K. Saroff D. Lorenzo A. Yuan M. Yankner B.A. Nat. Med. 1998; 4: 827-831Crossref PubMed Scopus (502) Google Scholar). These toxic effects of Aβ were age-dependent in rhesus macaques but did not appear in aging rats. Thus, aging primates may be more vulnerable to Aβ toxicity than aging rodents, possibly accounting for the relative absence of AD-type pathology in APP transgenic mouse models. The importance of Aβ aggregation in the mechanism of Aβ toxicity was noted in early cell culture studies (24Pike C.J. Walencewicz A.J. Glabe C.G. Cotman C.W. Eur. J. Pharmacol. 1991; 207: 367-368Crossref PubMed Scopus (267) Google Scholar, 25Busciglio J. Lorenzo A. Yankner B.A. Neurobiol. Aging. 1992; 13: 609-612Crossref PubMed Scopus (204) Google Scholar) and was supported by the finding that FAD mutations in APP increase generation of the highly aggregable Aβ42 peptide (8Suzuki N. Cheung T.T. Cai X.D. Odaka A. Otvos Jr., L. Eckman C. Golde T.E. Younkin S.G. Science. 1994; 264: 1336-1340Crossref PubMed Scopus (1358) Google Scholar). Recent studies suggest that low molecular weight oligomers are more toxic than the larger Aβ fibrils (26Roychaudhuri R. Yang M. Hoshi M.M. Teplow D.B. J. Biol. Chem. 2009; 284: 4749-4753Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar). The toxicity of Aβ oligomers was described by Klein and co-workers (27Lambert M.P. Barlow A.K. Chromy B.A. Edwards C. Freed R. Liosatos M. Morgan T.E. Rozovsky I. Trommer B. Viola K.L. Wals P. Zhang C. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6448-6453Crossref PubMed Scopus (3144) Google Scholar) in studies of small diffusible Aβ oligomers that they named ADDLs, which cause neuronal cell death in hippocampal slice cultures at nanomolar concentrations. Notably, ADDLs could inhibit hippocampal long-term potentiation, suggesting a potential role in memory impairment in AD. Evidence that Aβ oligomers could impair synaptic physiology in vivo came from experiments in which Aβ oligomers generated by APP-transfected Chinese hamster ovary cells were injected into the rat brain and impaired hippocampal long-term potentiation in vivo (28Walsh D.M. Klyubin I. Fadeeva J.V. Cullen W.K. Anwyl R. Wolfe M.S. Rowan M.J. Selkoe D.J. Nature. 2002; 416: 535-539Crossref PubMed Scopus (3721) Google Scholar). Injection of preparations enriched in Aβ dimers and trimers, but not monomers or fibrils, resulted in behavioral deficits in a food-related reinforcement learning paradigm. Rats that received multiple oligomer injections improved and did not show a deficit, suggesting that oligomers transiently impaired synaptic physiology but did not induce neurodegeneration. Whether the low molecular mass dimers and trimers were active or aggregated further to higher molecular mass forms upon injection into the brain was not resolved. Another study showed that a 56-kDa Aβ-immunoreactive species, a putative Aβ dodecamer, correlated with memory impairment in Tg2576 transgenic mice (29Lesne S. Koh M.T. Kotilinek L. Kayed R. Glabe C.G. Yang A. Gallagher M. Ashe K.H. Nature. 2006; 440: 352-357Crossref PubMed Scopus (2440) Google Scholar). This species, referred to by the authors as Aβ*56, was isolated from the transgenic mouse cortex and injected into the adult rat brain, resulting in transient deficits in memory retention. In aged transgenic mice, however, cognitive deficits did not clearly correlate with Aβ*56 levels, leading the authors to suggest that Aβ*56 may contribute to early cognitive deficits similar to those that occur in patients with mild cognitive impairment (29Lesne S. Koh M.T. Kotilinek L. Kayed R. Glabe C.G. Yang A. Gallagher M. Ashe K.H. Nature. 2006; 440: 352-357Crossref PubMed Scopus (2440) Google Scholar). 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