title: A monoclonal antibody against synthetic Aβ dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aβ.
abstract: Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid β-protein (Aβ) play an important role in Alzheimer's disease pathogenesis. Although the precise molecular identity of these soluble toxins remains unsettled, recent experiments suggest that sodium dodecyl sulfate (SDS)-stable Aβ dimers may be the basic building blocks of Alzheimer's disease-associated synaptotoxic assemblies and as such present an attractive target for therapeutic intervention. In the absence of sufficient amounts of highly pure cerebral Aβ dimers, we have used synthetic disulfide cross-linked dimers (free of Aβ monomer or fibrils) to generate conformation-specific monoclonal antibodies. These dimers aggregate to form kinetically trapped protofibrils, but do not readily form fibrils. We identified two antibodies, 3C6 and 4B5, which preferentially bind assemblies formed from covalent Aβ dimers, but do not bind to Aβ monomer, amyloid precursor protein, or aggregates formed by other amyloidogenic proteins. Monoclonal antibody 3C6, but not an IgM isotype-matched control antibody, ameliorated the plasticity-disrupting effects of Aβ extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant Aβ assemblies. These data prove the usefulness of covalent dimers and their assemblies as immunogens and recommend further investigation of the therapeutic and diagnostic utility of monoclonal antibodies raised to such assemblies.
authors.affiliation: Laboratory for Neurodegenerative Research, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. bonuallain@partners.org
authors.forename: Brian
authors.initials: B
authors.lastname: O'Nuallain
authors.forename: Igor
authors.initials: I
authors.lastname: Klyubin
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Mc Donald
authors.forename: James S
authors.initials: JS
authors.lastname: Foster
authors.forename: Alfred
authors.initials: A
authors.lastname: Welzel
authors.forename: Andrew
authors.initials: A
authors.lastname: Barry
authors.forename: Richard K
authors.initials: RK
authors.lastname: Dykoski
authors.forename: James P
authors.initials: JP
authors.lastname: Cleary
authors.forename: Martijn F B G
authors.initials: MF
authors.lastname: Gebbink
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D001923:Brain Chemistry; D003432:Cross-Linking Reagents; D004591:Electrophoresis, Polyacrylamide Gel; D055724:Electrophysiological Phenomena; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D047468:Immunoprecipitation; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects*; D011485:Protein Binding; D013569:Synapses / Q000187:drug effects*; D014020:Tissue Extracts / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D003432:Cross-Linking Reagents; D007075:Immunoglobulin M; D014020:Tissue Extracts