Nature Medicine8, 1263 - 1269 (2002)
Published online: 15 October 2002; | doi:10.1038/nm790
Therapeutically effective antibodies against amyloid- peptide target amyloid- residues 4−10 and inhibit cytotoxicity and fibrillogenesis
J. McLaurin1, 2, R. Cecal3, M.E. Kierstead1, 2, X. Tian3, A.L. Phinney1, M. Manea3, J.E. French1, M.H.L. Lambermon1, A.A. Darabie1, M.E. Brown1, C. Janus1, M.A. Chishti1, P. Horne1, D. Westaway1, 2, P.E. Fraser1, 4, H.T.J. Mount1, 5, M. Przybylski3
& P. St George-Hyslop1, 5
1
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
2
Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
3
Department of Chemistry, Laboratory of Analytical Chemistry, University of Konstanz, Germany
4
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
5
Department of Medicine, University of Toronto, and University Health Network/Toronto Western Hospital, Toronto, Ontario, Canada
Immunization of transgenic mouse models of Alzheimer disease using amyloid- peptide (A) reduces both the Alzheimer disease−like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with A42 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 A42, and that these antibodies inhibit both A 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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