Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer Disease 论文

摘要

Accumulation of amyloid-β (Aβ) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is thought to be a later downstream event. It is now well established that Aβ exists as monomers, oligomers, and fibrils. To study the temporal profile of Aβ oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation of plaques and tangles and cognitive impairments. We show that SDS-resistant Aβ oligomers accumulate in an age-dependent fashion, and we present evidence to show that oligomerization of Aβ appears to first occur intraneuronally. Finally, we show that a single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear Aβ pathology, and more importantly, tau pathology. Therefore, Aβ oligomers may play a role in the induction of tau pathology, making the interference of Aβ oligomerization a valid therapeutic target. Accumulation of amyloid-β (Aβ) is one of the earliest molecular events in Alzheimer disease (AD), whereas tau pathology is thought to be a later downstream event. It is now well established that Aβ exists as monomers, oligomers, and fibrils. To study the temporal profile of Aβ oligomer formation in vivo and to determine their interaction with tau pathology, we used the 3xTg-AD mice, which develop a progressive accumulation of plaques and tangles and cognitive impairments. We show that SDS-resistant Aβ oligomers accumulate in an age-dependent fashion, and we present evidence to show that oligomerization of Aβ appears to first occur intraneuronally. Finally, we show that a single intrahippocampal injection of a specific oligomeric antibody is sufficient to clear Aβ pathology, and more importantly, tau pathology. Therefore, Aβ oligomers may play a role in the induction of tau pathology, making the interference of Aβ oligomerization a valid therapeutic target. Alzheimer disease (AD) 2The abbreviations used are: ADAlzheimer diseaseAβamyloid-βLTPlong term potentiation. is the most common neurodegenerative disorder, affecting ∼5 million Americans (1Hebert L.E. Scherr P.A. Bienias J.L. Bennett D.A. Evans D.A. Arch. Neurol. 2003; 60: 1119-1122Crossref PubMed Scopus (1947) Google Scholar). Neuropathologically, it is characterized by the accumulation of extracellular plaques, mainly comprised of a small peptide called amyloid-β (Aβ), and intracellular neurofibrillary tangles, consisting of aggregates of hyperphosphorylated tau protein (2Selkoe D.J. Physiol. Rev. 2001; 81: 741-766Crossref PubMed Scopus (5196) Google Scholar). Based on compelling genetic evidence, it has been postulated that pathological assemblies of Aβ are the cause of all forms of AD (3Hardy J. Selkoe D.J. 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Traditionally, Aβ has been viewed as being generated and secreted extracellularly, but it is also becoming increasingly apparent that some Aβ can be generated in different intracellular compartments, such as the endoplasmic reticulum and the trans-Golgi (7Cook D.G. Forman M.S. Sung J.C. Leight S. Kolson D.L. Iwatsubo T. Lee V.M. Doms R.W. Nat. Med. 1997; 3: 1021-1023Crossref PubMed Scopus (430) Google Scholar, 8Hartmann T. Bieger S.C. Bruhl B. Tienari P.J. Ida N. Allsop D. Roberts G.W. Masters C.L. Dotti C.G. Unsicker K. Beyreuther K. Nat. Med. 1997; 3: 1016-1020Crossref PubMed Scopus (646) Google Scholar, 9Wild-Bode C. Yamazaki T. Capell A. Leimer U. Steiner H. Ihara Y. Haass C. J. Biol. Chem. 1997; 272: 16085-16088Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 10Xu H. Sweeney D. Wang R. Thinakaran G. Lo A.C. Sisodia S.S. Greengard P. Gandy S. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3748-3752Crossref PubMed Scopus (254) Google Scholar, 11Skovronsky D.M. 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A. 1998; 95: 6448-6453Crossref PubMed Scopus (3144) Google Scholar). Moreover, Aβ oligomers appear to interfere with many critical neuronal activities, including inhibiting long term potentiation (LTP) in organotypic hippocampal slices (18Lambert 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, 19Wang H.W. Pasternak J.F. Kuo H. Ristic H. Lambert M.P. Chromy B. Viola K.L. Klein W.L. Stine W.B. Krafft G.A. Trommer B.L. Brain Res. 2002; 924: 133-140Crossref PubMed Scopus (492) Google Scholar). Aβ oligomers can also cause calcium dysregulation and membrane disruption, thus interfering with overall cell functioning (20Demuro A. Mina E. Kayed R. Milton S.C. Parker I. Glabe C.G. J. Biol. Chem. 2005; 280: 17294-17300Abstract Full Text Full Text PDF PubMed Scopus (852) Google Scholar, 21Kayed R. Sokolov Y. Edmonds B. McIntire T.M. Milton S.C. Hall J.E. Glabe C.G. J. Biol. Chem. 2004; 279: 46363-46366Abstract Full Text Full Text PDF PubMed Scopus (779) Google Scholar). The toxicity of Aβ oligomers has also been shown in vivo. In particular, intracerebroventricular injection of oligomers inhibits LTP (22Walsh 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) and specifically disrupts cognitive function (23Cleary J.P. Walsh D.M. Hofmeister J.J. Shankar G.M. Kuskowski M.A. Selkoe D.J. Ashe K.H. Nat. Neurosci. 2005; 8: 79-84Crossref PubMed Scopus (1500) Google Scholar). Importantly, the concomitant injection of the anti-Aβ antibody 6E10 with Aβ oligomers neutralizes the oligomer-induced LTP dysfunction (24Klyubin I. Walsh D.M. Lemere C.A. Cullen W.K. Shankar G.M. Betts V. Spooner E.T. Jiang L. Anwyl R. Selkoe D.J. Rowan M.J. Nat. Med. 2005; 11: 556-561Crossref PubMed Scopus (452) Google Scholar). These data strongly support the idea that oligomers represent a fundamental species responsible for mediating Aβ toxicity in AD (2Selkoe D.J. Physiol. Rev. 2001; 81: 741-766Crossref PubMed Scopus (5196) Google Scholar, 16Klein W.L. Neurochem. Int. 2002; 41: 345-352Crossref PubMed Scopus (488) Google Scholar). Given the critical role that Aβ oligomers appear to play in the pathogenesis of AD, we sought to understand their genesis in an in vivo model of AD. We used the 3xTg-AD mice, which develop an age-dependent accumulation of both plaques and tangles in AD-relevant brain regions (25Oddo S. Caccamo A. Shepherd J.D. Murphy M.P. Golde T.E. Kayed R. Metherate R. Mattson M.P. Akbari Y. LaFerla F.M. Neuron. 2003; 39: 409-421Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar). We first charted the temporal relationship between Aβ monomers, oligomers, and fibrils formation. Of particular relevance, we found that oligomerization of Aβ appears to commence intraneuronally in the 3xTg-AD brains, a finding consistent with other in vitro and in vivo studies (26Kawarabayashi T. Shoji M. Younkin L.H. Wen-Lang L. Dickson D.W. Murakami T. Matsubara E. Abe K. Ashe K.H. Younkin S.G. J. Neurosci. 2004; 24: 3801-3809Crossref PubMed Scopus (299) Google Scholar, 27Takahashi R.H. Almeida C.G. Kearney P.F. Yu F. Lin M.T. Milner T.A. Gouras G.K. J. Neurosci. 2004; 24: 3592-3599Crossref PubMed Scopus (381) Google Scholar, 28Walsh D.M. Tseng B.P. Rydel R.E. Podlisny M.B. Selkoe D.J. Biochemistry. 2000; 39: 10831-10839Crossref PubMed Scopus (426) Google Scholar). As we previously showed that the of the Aβ pathology but also forms of tau pathology S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar), we studies and showed that the of an Aβ antibody is also to the tau pathology in These that the of Aβ oligomers may be a in the of the tau pathology. previously the of the 3xTg-AD (25Oddo S. Caccamo A. Shepherd J.D. Murphy M.P. Golde T.E. Kayed R. Metherate R. Mattson M.P. Akbari Y. LaFerla F.M. Neuron. 2003; 39: 409-421Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar). the 3xTg-AD by and the of the from from 3xTg-AD and in with a The to the and for The used for and the protein and with to the the brain to a membrane and the brain in from for and by from and to a in a of for with the in for and with the antibody for The in for and for with and from 3xTg-AD and for in a and in in The for in in for to the The antibody with and with the antibody for with the the in the antibody in on and with and with of of and in a with a of the an antibody or the a to a The with to and to the The of injection which the in for an to for on a from and in for to to the in with the of for the and of and by the to and in experimental by of or The of has the of the role of oligomers in the pathogenesis AD. In this study we used antibody which is and of molecular Aβ oligomers Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, L. L. Wang D.L. Klein W.L. J. Neurosci. 2003; PubMed Scopus Google Scholar), and antibody which is for molecular Aβ oligomers R. E. J.L. McIntire T.M. Milton S.C. Cotman C.W. Glabe C.G. Science. 2003; PubMed Scopus Google Scholar). of with Aβ monomers or protein Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, R. E. J.L. McIntire T.M. Milton S.C. Cotman C.W. Glabe C.G. Science. 2003; PubMed Scopus Google Scholar). Aβ first the temporal profile of Aβ oligomers in the brain of the 3xTg-AD both and from 3xTg-AD and in and the to a which with the and of the between the 3xTg-AD and that Aβ oligomers have to the all there an age-dependent in and in the 3xTg-AD first apparent by of and oligomerization of Aβ between and of we found that the of both and and of with the and the for this in oligomer is it may be of an in Aβ that (see This a as between and we found an age-dependent in Aβ oligomers in the 3xTg-AD and Aβ oligomers appear to be as SDS-resistant species have been from and cell (22Walsh 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, Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, C.A. S.J. M.J. Beyreuther K. Masters C.L. Neurol. PubMed Scopus Google Scholar, M.P. Viola K.L. Chromy B.A. Chang L. Morgan T.E. Yu J. D.L. Krafft G.A. Finch C.E. Klein W.L. J. Neurochem. 2001; PubMed Scopus Google Scholar). We SDS-resistant Aβ oligomers also be from the 3xTg-AD and by and of protein in we SDS-resistant Aβ and in brain from by 6E10 We to Aβ or in this particular Aβ oligomers are SDS-resistant their is for by a These data that the SDS-resistant oligomers in an age-dependent fashion in the 3xTg-AD and are in from several in vitro studies that Aβ oligomers may be a to however, studies have also the that Aβ oligomers be more and fibrils Biochemistry. 2003; 42: PubMed Scopus Google Scholar). To determine the temporal relationship between Aβ species in we charted their accumulation in the of the 3xTg-AD antibody 6E10 all forms of molecular Aβ oligomers the L. L. Wang D.L. Klein W.L. J. Neurosci. 2003; PubMed Scopus Google Scholar), and Aβ We on the this brain is by Aβ pathology in both AD and in the 3xTg-AD the well of the the study of the temporal of Aβ of apparent with antibody but with or that the of Aβ exists in a this of 6E10 and first apparent that oligomerization of Aβ intraneuronally between of (see also by Aβ oligomers are apparent in the we found a in extracellular and the antibody between oligomers and we the that some of the shown in is in of an with with that by that the of the extracellular shown in is most extracellular Aβ there is an age-dependent in in the from intracellular to extracellular between and that protein shown in the in in which may have some Aβ for the this with the The of extracellular Aβ oligomers appears to occur to extracellular plaques in vivo evidence that oligomers represent an to formation. data the that a of Aβ oligomers can be more or that can be of oligomers show different from or of the 3xTg-AD with and a antibody and As a of the with the antibody are also for as this antibody Aβ as however, we found a of that are for in that oligomers in different one the of Aβ is and one it is for is and for is To the of Aβ oligomers, we from the 3xTg-AD with and and We found that the oligomeric Aβ in the very that are in an intracellular with the antibody We found that a of by the antibody also for as Aβ as well however, we found a of that for Aβ specific These data that oligomers in different one the of Aβ is and one it is It is that different represent different of Aβ and be to of Aβ with but evidence that Aβ and tau pathology may As of to the of this interaction and to which form of Aβ may be we first there between Aβ oligomers and tau in vivo. from and 3xTg-AD with and These tau accumulation in the is the earliest of tau pathology in the 3xTg-AD mice, which is first apparent by of the pathology is and apparent with different and also with several tau (25Oddo S. Caccamo A. Shepherd J.D. Murphy M.P. Golde T.E. Kayed R. Metherate R. Mattson M.P. Akbari Y. LaFerla F.M. Neuron. 2003; 39: 409-421Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar). that there is some but between the and In we found evidence of and in These that Aβ oligomers with tau The of Aβ oligomers with tau pathology may be or the that Aβ can the tau pathology, it is to that Aβ oligomers intraneuronally or the may to the of the tau pathology. Aβ as as Aβ previously showed that a single injection of an anti-Aβ antibody Aβ from the of the 3xTg-AD mice, which to the in tau pathology S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar). As it is that Aβ species may also in of we the of an Aβ antibody on the of the Aβ and tau pathology. We of antibody the of 3xTg-AD This antibody used it is for oligomeric whereas between oligomers and fibrils. We found that a single of antibody the Aβ pathology in the the injection the of Aβ oligomers to the of the tau pathology in the of neurons of Aβ or tau pathology in the that as an and We also 3xTg-AD with or an antibody and found that of on the Aβ and tau pathology These data strongly that Aβ oligomers may be between Aβ and tau pathology. LTP (18Lambert 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, 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) and cognitive (23Cleary J.P. Walsh D.M. Hofmeister J.J. Shankar G.M. Kuskowski M.A. Selkoe D.J. Ashe K.H. Nat. Neurosci. 2005; 8: 79-84Crossref PubMed Scopus (1500) Google Scholar), Aβ oligomers can with tau pathology. of the earliest that in AD is a it has been that this may be by which may be a consequence of the accumulation of soluble Aβ oligomers W.L. Krafft G.A. Finch C.E. Neurosci. 2001; 24: Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. Science. 2002; PubMed Scopus Google Scholar). This hypothesis is by the of oligomers from AD Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, C.A. S.J. M.J. Beyreuther K. Masters C.L. Neurol. PubMed Scopus Google Scholar). In particular, and C.A. S.J. M.J. Beyreuther K. Masters C.L. Neurol. PubMed Scopus Google Scholar) showed that this soluble form of Aβ with the of the Aβ oligomers from AD brains, or cell are to common such as D.M. Tseng B.P. Rydel R.E. Podlisny M.B. Selkoe D.J. Biochemistry. 2000; 39: 10831-10839Crossref PubMed Scopus (426) Google Scholar, Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, C.A. S.J. M.J. Beyreuther K. Masters C.L. Neurol. PubMed Scopus Google Scholar, M.P. Viola K.L. Chromy B.A. Chang L. Morgan T.E. Yu J. D.L. Krafft G.A. Finch C.E. Klein W.L. J. Neurochem. 2001; PubMed Scopus Google Scholar, M.B. B.L. R.E. Teplow D.B. Selkoe D.J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this we showed that the 3xTg-AD develop SDS-resistant oligomers in a progressive that are This is that it has been that Aβ oligomers may be a to but that interfere with neuronal function Biochemistry. 2003; 42: PubMed Scopus Google Scholar). of the of this that Aβ oligomerization intraneuronally. These data are consistent with data that Aβ oligomerization also in neurons and in other neuronal cell and in transgenic R.H. Almeida C.G. Kearney P.F. Yu F. Lin M.T. Milner T.A. Gouras G.K. J. Neurosci. 2004; 24: 3592-3599Crossref PubMed Scopus (381) Google Scholar, 28Walsh D.M. Tseng B.P. Rydel R.E. Podlisny M.B. Selkoe D.J. Biochemistry. 2000; 39: 10831-10839Crossref PubMed Scopus (426) Google Scholar). studies have shown that Aβ a role in the of the disease in Ref. 12Tseng B.P. Kitazawa M. LaFerla F.M. Curr. Alzheimer Res. 2004; 1: 231-239Crossref PubMed Scopus (61) Google Scholar). In particular, we previously showed that the 3xTg-AD have a of to brain regions that accumulate Aβ S. Caccamo A. K. L. Chen Y. F.M. LaFerla F.M. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). Moreover, we showed that 3xTg-AD have LTP and cognitive by Aβ (25Oddo S. Caccamo A. Shepherd J.D. Murphy M.P. Golde T.E. Kayed R. Metherate R. Mattson M.P. Akbari Y. LaFerla F.M. Neuron. 2003; 39: 409-421Abstract Full Text Full Text PDF PubMed Scopus (3229) Google Scholar, S. J.L. LaFerla F.M. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). data strongly that Aβ oligomers may be responsible for the of and the LTP and cognitive in the 3xTg-AD the other there is also evidence that Aβ oligomers can as extracellular for Y. Chang L. Viola K.L. Lacor P.N. Lambert M.P. Finch C.E. Krafft G.A. Klein W.L. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar, P.N. Chang L. Fernandez S.J. Y. Viola K.L. Lambert M.P. Velasco P.T. Finch C.E. Krafft G.A. Klein W.L. J. Neurosci. 2004; 24: PubMed Scopus Google Scholar). These are the of Aβ oligomers, it is that are the interfering with cell and in the extracellular can as a and interfere with neuronal Moreover, we the that some Aβ oligomers may also form and to Aβ toxicity and formation. studies be to determine the of the of Aβ oligomers to the of and the LTP and cognitive in the 3xTg-AD the data with other studies that Aβ oligomers LTP and cognitive (18Lambert 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, 19Wang H.W. Pasternak J.F. Kuo H. Ristic H. Lambert M.P. Chromy B. Viola K.L. Klein W.L. Stine W.B. Krafft G.A. Trommer B.L. Brain Res. 2002; 924: 133-140Crossref PubMed Scopus (492) Google Scholar, 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, J.P. Walsh D.M. Hofmeister J.J. Shankar G.M. Kuskowski M.A. Selkoe D.J. Ashe K.H. Nat. Neurosci. 2005; 8: 79-84Crossref PubMed Scopus (1500) Google Scholar), strongly in of this We and data to show that Aβ and tau in vivo (4Lewis J. Dickson D.W. Lin W.L. Chisholm L. Corral A. Jones G. Yen S.H. Sahara N. Skipper L. Yager D. Eckman C. Hardy J. Hutton M. McGowan E. Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1282) Google Scholar, 5Gotz J. Chen F. van Dorpe J. Nitsch R.M. Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1288) Google Scholar, 6Oddo S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar). In particular, we have shown that anti-Aβ clear both intracellular and extracellular Aβ and to the of the tau pathology S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar). In this we showed that a single intrahippocampal injection of the antibody intracellular Aβ In this regard, we have previously shown that Aβ can also be by other anti-Aβ S. Billings L. Kesslak J.P. Cribbs D.H. LaFerla F.M. Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar, S. J.L. LaFerla F.M. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The the of Aβ to be of a relationship between and extracellular of Aβ S. Caccamo A. LaFerla F.M. J. Google Scholar). the injection of the Aβ antibody to the of tau pathology as well as Aβ pathology. These data strongly that Aβ oligomers may represent a between Aβ and tau pathology. It has been shown that Aβ neutralizes Aβ oligomers, thus the oligomer-induced LTP (24Klyubin I. Walsh D.M. Lemere C.A. Cullen W.K. Shankar G.M. Betts V. Spooner E.T. Jiang L. Anwyl R. Selkoe D.J. Rowan M.J. Nat. Med. 2005; 11: 556-561Crossref PubMed Scopus (452) Google Scholar). Walsh and D.M. M. Podlisny M.B. Shankar G.M. Fadeeva J.V. D.M. Selkoe D.J. J. Neurosci. 2005; PubMed Scopus Google Scholar) showed that the oligomer-induced LTP can be by small that Aβ In of data and the it is to that Aβ oligomerization is a valid therapeutic to or AD as Aβ oligomer formation can the LTP and and the tau pathology. This last is very as tau pathology is sufficient to cause in for AD therapeutic to be it to the of tau pathology as well as Aβ pathology.