期刊
JOURNAL OF NEUROCHEMISTRY
卷 119, 期 1, 页码 189-201出版社
WILEY
DOI: 10.1111/j.1471-4159.2011.07389.x
关键词
Aggregates; Alzheimer's disease; amyloid; Immunotherapy; Long-term potentiation; Protofibrils
资金
- Health Research Board [RP/2008/30]
- Science Foundation Ireland
- National Institutes of Health [IRO1A-GO27443]
- Health Research Board (HRB) [RP-2008-30] Funding Source: Health Research Board (HRB)
Diverse lines of evidence indicate that pre-fibrillar, diffusible assemblies of the amyloid beta-protein (A beta) 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 A beta 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 A beta dimers, we have used synthetic disulfide cross-linked dimers (free of A beta 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 A beta dimers, but do not bind to A beta 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 A beta extracted from the aqueous phase of Alzheimer's disease brain, thus suggesting that 3C6 targets pathogenically relevant A beta 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.
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