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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1282963
- author
- Sun, Binggui
; Zhou, Yungui
; Halabisky, Brian
; Lo, Iris
; Cho, Seo-Hyun
; Mueller-Steiner, Sarah
; Devidze, Nino
; Wang, Xin
; Grubb, Anders
LU
and Gan, Li
- organization
- publishing date
- 2008
- 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
- pmid:18957217
- 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
- 2016-04-01 12:38:26
- date last changed
- 2023-01-03 19:25:38
@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}},
doi = {{10.1016/j.neuron.2008.10.001}},
volume = {{60}},
year = {{2008}},
}