Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 386, Issue 2, Pages 284-288Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2009.05.131
Keywords
Beta-amyloid; Cathepsin B; Gene knockout; Amyloid precursor protein; Protease
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Funding
- NIA/NIH [R21 AG027446, 1R44AG032784]
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Neurotoxic beta-amyloid (A beta) peptides participate in Alzheimer's disease (AD); therefore, reduction of A beta generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human A beta may identify targets for reducing A beta. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decreases in brain A beta 40 and A beta 42 by 67% and decreases in levels of the C-terminal beta-secretase fragment (CTF beta) derived from APP. In contrast, knockout of cathepsin B in mice expressing hAPP with the rare Swedish (Swe) and Indiana (Ind) mutations had no effect on A beta. The difference in reduction of A beta in hAPPwt mice, but not in hAPPSwe/Ind mice, shows that the transgenic model can affect cathepsin B gene knockout results. Since most AD patients express hAPPwt, these data validate cathepsin B as a target for development of inhibitors to lower A beta in AD. (C) 2009 Elsevier Inc. All rights reserved.
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