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首页> 外文期刊>Neuron >Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.
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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.

机译：胱抑素C-蛋白酶B轴调节阿尔茨海默氏病动物模型中的淀粉样β水平和相关的神经元缺陷。

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摘要

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.
机译：淀粉样蛋白β（Abeta）肽降解受损可能导致Abeta积累，这是阿尔茨海默氏病（AD）的早期触发因素。尚不清楚Abeta降解酶的调控方式。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）（一种最近发现的Abeta降解酶）。 CST3多态性与迟发性散发性AD的风险增加有关。在这里，我们确定CysC为体内CatB诱导的Abeta降解的关键抑制剂。 hAPP-J20小鼠中CST3的遗传切除显着降低了可溶性Abe​​ta水平，Abeta1-42的相对丰度和噬菌斑负荷。去除CysC还可以减轻Abeta相关的认知缺陷和行为异常，并恢复海马的突触可塑性。重要的是，CysC降低的有益作用在CatB无效背景下被取消，提供了直接的证据表明CysC通过抑制CatB诱导的Abeta降解来调节可溶性Abe​​ta和与Abeta相关的神经元缺陷。

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