Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein

Research output: Contribution to journalArticle


title = "Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein",
abstract = "Accumulation of amyloid-beta (A beta), believed to be a key trigger of Alzheimer disease (AD), could result from impaired clearance mechanisms. Previously, we showed that the cysteine protease cathepsin B (CatB) degrades A beta, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the A beta-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers A beta levels by enhancing CatB-mediated A beta degradation in hAPP(FAD) mice. However, because a vast majority of AD patients do not carry familial mutations, we investigated how the CysC-CatB axis affects A beta levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total A beta and A beta 42 levels in hAPP(WT) mice, whereas CatB deletion increased A beta levels. To determine whether neuron-derived CatB degrades A beta in vivo, we generated transgenic mice overexpressing CatB under the control of a neuron-specific enolase promoter. Enhancing neuronal CatB activity in hAPP(WT) mice significantly lowered A beta 42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of A beta 42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower A beta, especially A beta 42, in AD patients with or without familial mutations.",
author = "Chao Wang and Binggui Sun and Yungui Zhou and Anders Grubb and Li Gan",
year = "2012",
doi = "10.1074/jbc.M112.371641",
language = "English",
volume = "287",
pages = "39834--39841",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "ASBMB",
number = "47",