Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4-10 and inhibit cytotoxicity and fibrillogenesis

被引:370
作者
McLaurin, J [1 ]
Cecal, R
Kierstead, ME
Tian, X
Phinney, AL
Manea, M
French, JE
Lambermon, MHL
Darabie, AA
Brown, ME
Janus, C
Chishti, MA
Horne, P
Westaway, D
Fraser, PE
Mount, HTJ
Przybylski, M
St George-Hyslop, P
机构
[1] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada
[2] Univ Toronto, Dept Lab Med, Toronto, ON, Canada
[3] Univ Toronto, Dept Pathobiol, Toronto, ON, Canada
[4] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
[5] Univ Konstanz, Dept Chem, Analyt Chem Lab, D-7750 Constance, Germany
[6] Univ Toronto, Dept Med, Toronto, ON, Canada
[7] Univ Hlth Network, Toronto Western Hosp, Toronto, ON, Canada
关键词
D O I
10.1038/nm790
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta pepticle (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta(42) 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 Abeta(42), and that these antibodies inhibit both Abeta 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.
引用
收藏
页码:1263 / 1269
页数:7
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