Title | Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. |
Publication Type | Journal Article |
Year of Publication | 2008 |
Authors | Sun B, Zhou Y, Halabisky B, Lo I, Cho S-H, Mueller-Steiner S, Devidze N, Wang X, Grubb A, Gan L |
Journal | Neuron |
Volume | 60 |
Issue | 2 |
Pagination | 247-57 |
Date Published | 2008 Oct 23 |
ISSN | 1097-4199 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Cathepsin B, Cystatin C, Genetic Predisposition to Disease, Mice, Mice, Knockout, Peptide Fragments, Plaque, Amyloid, Polymorphism, Genetic |
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. |
DOI | 10.1016/j.neuron.2008.10.001 |
Alternate Journal | Neuron |
PubMed ID | 18957217 |
PubMed Central ID | PMC2755563 |
Grant List | C06 RR018928 / RR / NCRR NIH HHS / United States R21 AG024447-02 / AG / NIA NIH HHS / United States AG024447 / AG / NIA NIH HHS / United States R21 AG024447 / AG / NIA NIH HHS / United States R21 AG024447-01 / AG / NIA NIH HHS / United States |