期刊
BIOLOGICAL CHEMISTRY
卷 391, 期 8, 页码 861-872出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/BC.2010.110
关键词
Alzheimer's disease; beta-amyloid; cathepsin B; cleavage site; inhibitor; memory; pharmacogenetics; protease; transgenic AD mice
资金
- NIA NIH HHS [1R44AG032784, R44 AG030865, R21 AG027446, R44 AG032784] Funding Source: Medline
- NIDA NIH HHS [R01 DA004271] Funding Source: Medline
Beta-amyloid (A beta) in the brain is a major factor involved in Alzheimer's disease (AD) that results in severe memory deficit. Our recent studies demonstrate pharmacogenetic differences in the effects of inhibitors of cathepsin B to improve memory and reduce A beta in different mouse models of AD. The inhibitors improve memory and reduce brain A beta in mice expressing the wild-type (WT) beta-secretase site of human APP, expressed in most AD patients. However, these inhibitors have no effect in mice expressing the rare Swedish (Swe) mutant amyloid precursor protein (APP). Knockout of the cathepsin B decreased brain A beta in mice expressing WT APP, validating cathepsin B as the target. The specificity of cathepsin B to cleave the WT beta-secretase site, but not the Swe mutant site, of APP for A beta production explains the distinct inhibitor responses in the different AD mouse models. In contrast to cathepsin B, the BACE1 beta-secretase prefers to cleave the Swe mutant site. Discussion of BACE1 data in the field indicate that they do not preclude cathepsin B as also being a beta-secretase. Cathepsin B and BACE1 could participate jointly as beta-secretases. Significantly, the majority of AD patients express WT APP and, therefore, inhibitors of cathepsin B represent candidate drugs for AD.
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