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

SummaryImpaired degradation of amyloid beta (Aβ) peptides could lead to Aβ accumulation, an early trigger of Alzheimer's disease (AD). How Aβ-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 Aβ-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 Aβ degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Aβ levels, the relative abundance of Aβ1-42, and plaque load. CysC removal also attenuated Aβ-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 Aβ and Aβ-associated neuronal deficits through inhibiting CatB-induced Aβ degradation.