Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein
Wang, Chao ; Sun, Binggui ; Zhou, Yungui ; Grubb, Anders LU
and Gan, Li
(2012)
In Journal of Biological Chemistry
287(47).
p.39834-39841
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3243956
- author
- Wang, Chao
; Sun, Binggui
; Zhou, Yungui
; Grubb, Anders
LU
and Gan, Li
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 287
- issue
- 47
- pages
- 39834 - 39841
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000311233800051
- pmid:23024364
- scopus:84873964654
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M112.371641
- language
- English
- LU publication?
- yes
- id
- 2ebd3c1e-4c32-4530-b78a-4bdeeb8bbbe7 (old id 3243956)
- date added to LUP
- 2016-04-01 10:01:09
- date last changed
- 2023-01-02 00:25:30
@article{2ebd3c1e-4c32-4530-b78a-4bdeeb8bbbe7,
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 = {{Wang, Chao and Sun, Binggui and Zhou, Yungui and Grubb, Anders and Gan, Li}},
issn = {{1083-351X}},
language = {{eng}},
number = {{47}},
pages = {{39834--39841}},
publisher = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Cathepsin B Degrades Amyloid-beta in Mice Expressing Wild-type Human Amyloid Precursor Protein}},
url = {{http://dx.doi.org/10.1074/jbc.M112.371641}},
doi = {{10.1074/jbc.M112.371641}},
volume = {{287}},
year = {{2012}},
}