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Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease

Sun, Binggui; Zhou, Yungui; Halabisky, Brian; Lo, Iris; Cho, Seo-Hyun; Mueller-Steiner, Sarah; Devidze, Nino; Wang, Xin; Grubb, Anders LU and Gan, Li (2008) In Neuron 60(2). p.247-257
Abstract
Impaired degradation of amyloid beta (A beta) peptides could lead to A beta accumulation, an early trigger of Alzheimer's disease (AD). How A beta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered A beta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced A beta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble A beta levels, the relative abundance of A beta l-42, and plaque load. CysC removal also attenuated A beta-associated cognitive deficits and... (More)
Impaired degradation of amyloid beta (A beta) peptides could lead to A beta accumulation, an early trigger of Alzheimer's disease (AD). How A beta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered A beta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced A beta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble A beta levels, the relative abundance of A beta l-42, and plaque load. CysC removal also attenuated A beta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble A beta and A beta-associated neuronal deficits through inhibiting CatB-induced A beta degradation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neuron
volume
60
issue
2
pages
247 - 257
publisher
Cell Press
external identifiers
  • wos:000260549300008
  • scopus:53849106834
ISSN
0896-6273
DOI
10.1016/j.neuron.2008.10.001
language
English
LU publication?
yes
id
fb06ba5c-a86b-46a4-8dc1-79b0cecbe70e (old id 1282963)
alternative location
http://www.sciencedirect.com/science/article/pii/S0896627308008386
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755563/
http://www.ncbi.nlm.nih.gov/pubmed/18957217
date added to LUP
2009-02-10 13:41:52
date last changed
2017-11-05 03:49:52
@article{fb06ba5c-a86b-46a4-8dc1-79b0cecbe70e,
  abstract     = {Impaired degradation of amyloid beta (A beta) peptides could lead to A beta accumulation, an early trigger of Alzheimer's disease (AD). How A beta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered A beta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced A beta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble A beta levels, the relative abundance of A beta l-42, and plaque load. CysC removal also attenuated A beta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble A beta and A beta-associated neuronal deficits through inhibiting CatB-induced A beta degradation.},
  author       = {Sun, Binggui and Zhou, Yungui and Halabisky, Brian and Lo, Iris and Cho, Seo-Hyun and Mueller-Steiner, Sarah and Devidze, Nino and Wang, Xin and Grubb, Anders and Gan, Li},
  issn         = {0896-6273},
  language     = {eng},
  number       = {2},
  pages        = {247--257},
  publisher    = {Cell Press},
  series       = {Neuron},
  title        = {Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease},
  url          = {http://dx.doi.org/10.1016/j.neuron.2008.10.001},
  volume       = {60},
  year         = {2008},
}