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标题：Gleevec inhibits β-amyloid production but not Notch cleavage
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作者：William J. Netzer ; Fei Dou ; Dongming Cai 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：21
页码：12444-12449
DOI：10.1073/pnas.1534745100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Amyloid-{beta} (A{beta}) peptides, consisting mainly of 40 and 42 aa (A{beta}40 and A{beta}42, respectively), are metabolites of the amyloid precursor protein and are believed to be major pathological determinants of Alzheimer's disease. The proteolytic cleavages that form the A{beta} N and C termini are catalyzed by {beta}-secretase and {gamma}-secretase, respectively. Here we demonstrate that {gamma}-secretase generation of A{beta} in an N2a cell-free system is ATP dependent. In addition, the Abl kinase inhibitor imatinib mesylate (Gleevec, or STI571), which targets the ATP-binding site of Abl and several other tyrosine kinases, potently reduces A{beta} production in the N2a cell-free system and in intact N2a cells. Both STI571 and a related compound, inhibitor 2, also reduce A{beta} production in rat primary neuronal cultures and in vivo in guinea pig brain. STI571 does not inhibit the {gamma}-secretase-catalyzed S3 cleavage of Notch-1. Furthermore, production of A{beta} and its inhibition by STI571 were demonstrated to occur to similar extents in both Abl-/- and WT mouse fibroblasts, indicating that the effect of STI571 on A{beta} production does not involve Abl kinase. The efficacy of STI571 in reducing A{beta} without affecting Notch-1 cleavage may prove useful as a basis for developing novel therapies for Alzheimer's disease.