Genetic cathepsin B deficiency reduces β-amyloid in transgenic mice expressing human wild-type amyloid precursor protein

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.