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

Depts of Neurosciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093-0744, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2009; 386(2):284-8. DOI: 10.1016/j.bbrc.2009.05.131
Source: PubMed


Neurotoxic beta-amyloid (Abeta) peptides participate in Alzheimer's disease (AD); therefore, reduction of Abeta generated from APP may provide a therapeutic approach for AD. Gene knockout studies in transgenic mice producing human Abeta may identify targets for reducing Abeta. This study shows that knockout of the cathepsin B gene in mice expressing human wild-type APP (hAPPwt) results in substantial decreases in brain Abeta40 and Abeta42 by 67% and decreases in levels of the C-terminal beta-secretase fragment (CTFbeta) 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 Abeta. The difference in reduction of Abeta 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 Abeta in AD.

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    • "Kif1a is a member of the kinesin family (KIFs) (Takemura et al., 1996) and has previously been connected to AD (Kondo et al., 2012). These microtubule-based motor proteins transport membrane organelles, mRNA, and proteins (Hirokawa et al., 2009). By transporting those complexes, KIFs play important roles in neuronal function and plasticity as well as morphogenesis and survival (Hirokawa et al., 2010). "
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