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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2011

Open Access 01-12-2011 | Research article

Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse

Authors: Ayumi Takamura, Yasuhide Okamoto, Takeshi Kawarabayashi, Tatsuki Yokoseki, Masao Shibata, Akihiro Mouri, Toshitaka Nabeshima, Hui Sun, Koji Abe, Tsuneo Urisu, Naoki Yamamoto, Mikio Shoji, Katsuhiko Yanagisawa, Makoto Michikawa, Etsuro Matsubara

Published in: Molecular Neurodegeneration | Issue 1/2011

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Abstract

Background

Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.

Results

To specifically target toxic AβOs in vivo, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.

Conclusion

Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.
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Literature
1.
Hardy J, Allsop D: Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991, 12: 383-388. 10.1016/0165-6147(91)90609-V.PubMedCrossRef
2.
Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J: Soluble amyloid β peptide concentration as a predictor of synaptic change in Alzheimer's disease. Am J Pathol. 1999, 155: 853-862. 10.1016/S0002-9440(10)65184-X.PubMedPubMedCentralCrossRef
3.
McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL: Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease. Ann Neurol. 1999, 46: 860-866. 10.1002/1531-8249(199912)46:6<860::AID-ANA8>3.0.CO;2-M.PubMedCrossRef
4.
Klein WL, Krafft GA, Finch CE: Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?. Trends Neurosci. 2001, 24: 219-224. 10.1016/S0166-2236(00)01749-5.PubMedCrossRef
5.
Selkoe DJ: Alzheimer's disease is a synaptic failure. Science. 2002, 298: 789-791. 10.1126/science.1074069.PubMedCrossRef
6.
Hass C, Selkoe DJ: Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nat Rev Mol Cell Biol. 2007, 8: 101-112. 10.1038/nrm2101.CrossRef
7.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T: Inflammation and Alzheimer's disease. Neurobiol Aging. 2000, 21: 383-421. 10.1016/S0197-4580(00)00124-X.PubMedPubMedCentralCrossRef
8.
Hardy JA, Higgins GA: Alzheimer's disease: the amyloid cascade hypothesis. Science. 1992, 256: 184-185. 10.1126/science.1566067.PubMedCrossRef
9.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE: Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA. 1998, 95: 6448-6453. 10.1073/pnas.95.11.6448.PubMedPubMedCentralCrossRef
10.
Dodart JC, Bales KR, Gannon KS, Greene SJ, DeMattos RB, Mathis C, DeLong CA, Wu S, Wu X, Holtzman DM, Paul SM: Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model. Nat Neurosci. 2002, 5: 452-457.PubMed
11.
Chromy BA, Nowak RJ, Lambert MP, Viola KL, Chang L, Velasco PT, Jones BW, Fernandez SJ, Lacor PN, Horowitz P, Finch CE, Krafft GA, Klein WL: Self-assembly of Aβ1-42 into globular neurotoxins. Biochemistry. 2003, 42: 12749-12760. 10.1021/bi030029q.PubMedCrossRef
12.
Kayed R, Head E, Thompson JL, Mclntire TM, Milton SC, Cotman CW, Glabe CG: Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003, 300: 486-489. 10.1126/science.1079469.PubMedCrossRef
13.
Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA: Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008, 372: 216-223. 10.1016/S0140-6736(08)61075-2.PubMedCrossRef
14.
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ: Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002, 16: 535-539. 10.1038/416535a.CrossRef
15.
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Walsh DM, Sabatini BL, Selkoe DJ: Amyloid-betaprotein dimers isolated directly from Alzheimer's brains impairsynaptic plasticity and memory. Nat Med. 2008, 14: 837-842. 10.1038/nm1782.PubMedPubMedCentralCrossRef
16.
Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL: Synaptic targeting by Alzheimer's-related amyloid β oligomers. J Neurosci. 2004, 24: 10191-10200. 10.1523/JNEUROSCI.3432-04.2004.PubMedCrossRef
17.
Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH: Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat Neurosci. 2005, 8: 79-84. 10.1038/nn1372.PubMedCrossRef
18.
Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006, 440: 352-357.PubMedCrossRef
19.
Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL: Alzheimer's disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA. 2003, 100: 10417-10422. 10.1073/pnas.1834302100.PubMedPubMedCentralCrossRef
20.
21.
Kayed R, Head E, Sarsoza F, Saing T, Cotman CW, Necula M, Margol L, Wu J, Breydo L, Thompson JL, Rasool S, Gurlo T, Butler P, Glabe CG: Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodeg. 2007, 2: 18-28. 10.1186/1750-1326-2-18.CrossRef
22.
Yamamoto N, Matsubara E, Maeda S, Minagawa H, Takashima A, Maruyama W, Michikawa M, Yanagisawa K: A ganglioside-induced toxic soluble Aβ assembly. Its enhanced formation from Aβ bearing the Arctic mutation. J Biol Chem. 2007, 282: 2646-2655. 10.1074/jbc.M606202200.PubMedCrossRef
23.
Hoshi M, Sato M, Matsumoto S, Noguchi A, Yasutake K, Yoshida N, Sato K: Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3β. Proc Natl Acad Sci USA. 2003, 100: 6370-6375. 10.1073/pnas.1237107100.PubMedPubMedCentralCrossRef
24.
Noguchi A, Matsumura S, Dezawa M, Tada M, Yanazawa M, Ito A, Akioka M, Kikuchi S, Sato M, Ideno S, Noda M, Fukunari A, Muramatsu S, Itokazu Y, Sato K, Takahashi H, Teplow DB, Nabeshima Y, Kakita A, Imahori K, Hoshi M: Isolation and characterization of patient-derived, toxic, high mass amyloid beta-protein (Abeta) assembly from Alzheimer disease brains. J Biol Chem. 2009, 284: 32895-905. 10.1074/jbc.M109.000208.PubMedPubMedCentralCrossRef
25.
Tero R, Takizawa M, Li YJ, Yamazaki M, Urisu T: Lipid membrane formation by vesicle fusion on silicon dioide surfaces modified with alkyl self-assembled monolayer islands. Langmuir. 2004, 20: 7526-7531. 10.1021/la0400306.PubMedCrossRef
26.
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH: Reversible memory loss in a mouse model of Alzheimer's disease. J Neurosci. 2002, 22: 6331-6335.PubMed
27.
Lee EB, Leng LZ, Zhang B, Kwong L, Trojanowski JQ, Lee VM: Targeting amyloid-β peptide (Aβ) oligomers by passive immunization with a conformation-selective monoclonal antibodies improves learning and memory in Aβ precursor protein (APP) transgenic mice. J Biol Chem. 2006, 281: 4292-4299. 10.1074/jbc.M511018200.PubMedCrossRef
28.
Mouri A, Noda Y, Hara H, Mizoguchi H, Tabira T, Nabeshim T: Oral vaccination with a viral vector containing Aβ cDNA attenuates age-related Aβ accumulation and memory deficits without causing inflammation in a mouse Alzheimer model. FASEB J. 2007, 21: 2135-2148. 10.1096/fj.06-7685com.PubMedCrossRef
29.
Schmued LC, Hopkins KJ, Fluoro-Jade B: A high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res. 2000, 874: 123-130. 10.1016/S0006-8993(00)02513-0.PubMedCrossRef
30.
Lambert MP, Viola KL, Chromy BA, Chang L, Morgan TE, Yu J, Venton DL, Krafft GA, Finch CE, Klein WL: Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies. J Neurochem. 2001, 79: 595-605. 10.1046/j.1471-4159.2001.00592.x.PubMedCrossRef
31.
Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL: Monoclonal antibodies that target pathological assemblies of Aβ. J Neurochem. 2007, 100: 23-35. 10.1111/j.1471-4159.2006.04157.x.PubMedCrossRef
32.
Kawarabayashi T, Shoji M, Younkin LH, Wen-Lang L, Dickson DW, Murakami T, Matsubara E, Abe K, Ashe KH, Younkin SG: Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2004, 24: 3801-3809. 10.1523/JNEUROSCI.5543-03.2004.PubMedCrossRef
33.
Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, Tolan DR, Selkoe DJ, Lemere CA: Intraneuronal Aβ42 accumulation in Down syndrome brain. Amyloid. 2002, 9: 88-102.PubMed
34.
Hu X, Crick SL, Bu G, Frieden C, Pappu RV, Lee JM: Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proc Natl Acad Sci USA. 2009, 106: 20324-20329. 10.1073/pnas.0911281106.PubMedPubMedCentralCrossRef
35.
Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H: A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010, 30: 4845-56. 10.1523/JNEUROSCI.5825-09.2010.PubMedCrossRef
36.
Matsubara E, Frangione B, Ghiso J: Characterization of apolipoprotein J-Alzheimer's A beta interaction. J Biol Chem. 1995, 270: 7563-7567. 10.1074/jbc.270.13.7563.PubMedCrossRef
Metadata
Title
Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
Authors
Ayumi Takamura
Yasuhide Okamoto
Takeshi Kawarabayashi
Tatsuki Yokoseki
Masao Shibata
Akihiro Mouri
Toshitaka Nabeshima
Hui Sun
Koji Abe
Tsuneo Urisu
Naoki Yamamoto
Mikio Shoji
Katsuhiko Yanagisawa
Makoto Michikawa
Etsuro Matsubara
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2011
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/1750-1326-6-20

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