Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.

TitleCystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2008
AuthorsSun B, Zhou Y, Halabisky B, Lo I, Cho S-H, Mueller-Steiner S, Devidze N, Wang X, Grubb A, Gan L
JournalNeuron
Volume60
Issue2
Pagination247-57
Date Published2008 Oct 23
ISSN1097-4199
KeywordsAlzheimer 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.

DOI10.1016/j.neuron.2008.10.001
Alternate JournalNeuron
PubMed ID18957217
PubMed Central IDPMC2755563
Grant ListC06 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