McLaurin J, Cecal R, Kierstead M E, Tian X, Phinney A L, Manea M, French J E, Lambermon M H L, Darabie A A, Brown M E, Janus C, Chishti M A, Horne P, Westaway D, Fraser P E, Mount H T J, Przybylski M, St George-Hyslop P
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Nat Med. 2002 Nov;8(11):1263-9. doi: 10.1038/nm790. Epub 2002 Oct 15.
Immunization of transgenic mouse models of Alzheimer disease using amyloid-beta peptide (Abeta) reduces both the Alzheimer disease-like neuropathology and the spatial memory impairments of these mice. However, a therapeutic trial of immunization with Abeta42 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 Abeta42, 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.
使用β淀粉样肽（Aβ）对阿尔茨海默病转基因小鼠模型进行免疫接种，可减少这些小鼠的阿尔茨海默病样神经病理学改变和空间记忆障碍。然而，一项在人体中使用Aβ42进行免疫接种的治疗试验被终止，因为一些患者出现了严重的脑膜脑炎细胞炎症反应。我们在此表明，小鼠中的有益作用源于选择性针对Aβ42第4至10位残基的抗体，并且这些抗体在不引发炎症反应的情况下抑制Aβ纤维形成和细胞毒性。这些发现为改进免疫接种抗原以及设计小分子模拟物作为替代疗法的尝试提供了基础。
