Sun Binggui, Zhou Yungui, Halabisky Brian, Lo Iris, Cho Seo-Hyun, Mueller-Steiner Sarah, Devidze Nino, Wang Xin, Grubb Anders, Gan Li
Gladstone Institute of Neurological Disease, University of California San Francisco, San Francisco, CA 94158, USA.
Neuron. 2008 Oct 23;60(2):247-57. doi: 10.1016/j.neuron.2008.10.001.
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.
淀粉样β（Aβ）肽降解受损会导致Aβ积累，这是阿尔茨海默病（AD）的早期触发因素。Aβ降解酶如何被调节在很大程度上仍不清楚。胱抑素C（CysC，CST3）是半胱氨酸蛋白酶的内源性抑制剂，包括组织蛋白酶B（CatB），后者是最近发现的一种Aβ降解酶。一种CST3多态性与晚发性散发性AD的风险增加有关。在此，我们确定CysC是体内CatB诱导的Aβ降解的关键抑制剂。在hAPP-J20小鼠中对CST3进行基因敲除显著降低了可溶性Aβ水平、Aβ1-42的相对丰度和斑块负荷。去除CysC还减轻了与Aβ相关的认知缺陷和行为异常，并恢复了海马体中的突触可塑性。重要的是，在CatB基因缺失的背景下，CysC减少的有益作用消失了，这提供了直接证据，表明CysC通过抑制CatB诱导的Aβ降解来调节可溶性Aβ和与Aβ相关的神经元缺陷。
