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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

På svenska

Author

  • Binggui Sun
  • Yungui Zhou
  • Brian Halabisky
  • Iris Lo
  • Seo-Hyun Cho
  • Sarah Mueller-Steiner
  • Nino Devidze
  • Xin Wang
  • Anders Grubb
  • Li Gan

Summary, in English

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.

Publishing year

2008

Language

English

Pages

247-257

Publication/Series

Neuron

Volume

60

Issue

2

Document type

Journal article

Publisher

Cell Press

Topic

  • Neurosciences

Status

Published

ISBN/ISSN/Other

  • ISSN: 0896-6273