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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)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
287
issue
47
pages
39834 - 39841
publisher
ASBMB
external identifiers
  • wos:000311233800051
  • 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
2013-01-07 09:33:15
date last changed
2017-08-27 03:08:42
@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    = {ASBMB},
  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},
  volume       = {287},
  year         = {2012},
}