| First Author | Wang C | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 47 | Pages | 39834-41 |
| PubMed ID | 23024364 | Mgi Jnum | J:316693 |
| Mgi Id | MGI:6837052 | Doi | 10.1074/jbc.M112.371641 |
| Citation | Wang C, et al. (2012) Cathepsin B degrades amyloid-beta in mice expressing wild-type human amyloid precursor protein. J Biol Chem 287(47):39834-41 |
| abstractText | Accumulation of amyloid-beta (Abeta), 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 Abeta, most likely by C-terminal truncation, in mice expressing human amyloid precursor protein with familial AD-linked mutations (hAPP(FAD)). In addition, the Abeta-degrading activity of CatB is inhibited by its endogenous inhibitor, cystatin C (CysC). Reducing CysC expression markedly lowers Abeta levels by enhancing CatB-mediated Abeta 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 Abeta levels in mice expressing wild-type hAPP (hAPP(WT)). Enhancing CatB activity by CysC deletion significantly lowered total Abeta and Abeta42 levels in hAPP(WT) mice, whereas CatB deletion increased Abeta levels. To determine whether neuron-derived CatB degrades Abeta 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 Abeta42 levels. The processing of hAPP(WT) was unaffected by increasing or ablating CatB activity. Thus, the CysC-CatB axis affects degradation of Abeta42 derived from hAPP lacking familial mutations. These findings support the notion that enhancing CatB activity could lower Abeta, especially Abeta42, in AD patients with or without familial mutations. |
