Cystatin C-Cathepsin B Axis Regulates Amyloid Beta Levels and Associated Neuronal Deficits in an Animal Model of Alzheimer's Disease

Research output: Contribution to journalArticle

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.

Details

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

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
Original languageEnglish
Pages (from-to)247-257
JournalNeuron
Volume60
Issue number2
Publication statusPublished - 2008
Publication categoryResearch
Peer-reviewedYes