Abstract
Immunization of transgenic mouse models of Alzheimer disease using amyloid-β peptide (Aβ) reduces both the Alzheimer disease–like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Aβ42 in humans was discontinued because a few patients developed significant meningo-encephalitic cellular inflammatory reactions. Here we show that beneficial effects in mice arise from antibodies selectively directed against residues 4–10 of Aβ42, and that these antibodies inhibit both Aβ fibrillogenesis and cytotoxicity without eliciting an inflammatory response. These findings provide the basis for improved immunization antigens as well as attempts to design small-molecule mimics as alternative therapies.
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Acknowledgements
We thank N. Wang for the synthesis of all peptides used in this study, N. Youhnovski and E. Damoc for expert assistance with the FT-ICR mass spectrometry, and the Electron Microscopy Suite at the University of Toronto for use of Hitachi 7000 electron microscope. This study was supported by the Ontario Alzheimer's Society (to P.H., P.E.F., D.W., H.M.&J.M.), Canadian Institutes of Health Research (to P.H., P.E.F., D.W., H.M.&J.M.), the Natural Sciences and Engineering Research Council of Canada (to J.M.), Howard Hughes Foundation (to P.H.), Canadian Genetic Diseases Network (to P.H.), the Scottish Rite Charitable Foundation (to P.E.F.&J.M.), the Deutsche Forschungsgemeinschaft (M.P.), Research & Arts Ministery Baden-Württemberg (M.P.) and the Alexander-von-Humboldt Foundation through a fellowship (X.T.).
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McLaurin, J., Cecal, R., Kierstead, M. et al. Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4–10 and inhibit cytotoxicity and fibrillogenesis. Nat Med 8, 1263–1269 (2002). https://doi.org/10.1038/nm790
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DOI: https://doi.org/10.1038/nm790
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