Abstract |
Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-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 Abeta-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 Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-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 Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.
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Authors | Binggui Sun, Yungui Zhou, Brian Halabisky, Iris Lo, Seo-Hyun Cho, Sarah Mueller-Steiner, Nino Devidze, Xin Wang, Anders Grubb, Li Gan |
Journal | Neuron
(Neuron)
Vol. 60
Issue 2
Pg. 247-57
(Oct 23 2008)
ISSN: 1097-4199 [Electronic] United States |
PMID | 18957217
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amyloid beta-Peptides
- Cystatin C
- Peptide Fragments
- amyloid beta-protein (1-42)
- Cathepsin B
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Topics |
- Alzheimer Disease
(genetics, metabolism, physiopathology)
- Amyloid beta-Peptides
(metabolism)
- Animals
- Brain
(metabolism, physiopathology)
- Cathepsin B
(metabolism)
- Cystatin C
(genetics, metabolism)
- Genetic Predisposition to Disease
(genetics)
- Mice
- Mice, Knockout
- Peptide Fragments
(metabolism)
- Plaque, Amyloid
(genetics, metabolism, pathology)
- Polymorphism, Genetic
(genetics)
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