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

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.

• Författare: Binggui Sun; Yungui Zhou; Brian Halabisky; Iris Lo; Seo-Hyun Cho; Sarah Mueller-Steiner; Nino Devidze; Xin Wang; Anders Grubb; Li Gan
• Avdelning/ar: Avdelningen för klinisk kemi och farmakologi
• Publiceringsår: 2008
• Språk: Engelska
• Sidor: 247-257
• Publikation/Tidskrift/Serie: Neuron
• Volym: 60
• Issue: 2
• Länkar: http://www.sciencedirect.com/science/article/pii/S0896627308008386; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755563/; http://www.ncbi.nlm.nih.gov/pubmed/18957217; http://dx.doi.org/10.1016/j.neuron.2008.10.001
• Dokumenttyp: Artikel i tidskrift
• Förlag: Cell Press
• Ämne: Neurosciences
• Status: Published
• ISBN/ISSN/Övrigt: ISSN: 0896-6273