Nathan S. Kline Institute, Orangeburg, NY, USA.
J Alzheimers Dis. 2010;19(3):885-94. doi: 10.3233/JAD-2010-1291.
Multiple studies suggest that cystatin C (CysC) has a role in Alzheimer's disease (AD) and a decrease in CysC secretion is linked to the disease in patients with a polymorphism in the CysC gene. CysC binds amyloid-beta (Abeta) and inhibits formation of Abeta fibrils and oligomers both in vitro and in mouse models of amyloid deposition. Here we studied the effect of CysC on cultured primary hippocampal neurons and a neuronal cell line exposed to either oligomeric or fibrillar cytotoxic forms of Abeta. The extracellular addition of the secreted human CysC together with preformed either oligomeric or fibrillar Abeta increased cell survival. While CysC inhibits Abeta aggregation, it does not dissolve preformed Abeta fibrils or oligomers. Thus, CysC has multiple protective effects in AD, by preventing the formation of the toxic forms of Abeta and by direct protection of neuronal cells from Abeta toxicity. Therapeutic manipulation of CysC levels, resulting in slightly higher concentrations than physiological could protect neuronal cells from cell death in AD.
多项研究表明胱抑素 C（CysC）在阿尔茨海默病（AD）中起作用，并且在 CysC 基因发生多态性的患者中，CysC 分泌减少与该疾病有关。CysC 与淀粉样蛋白-β（Abeta）结合，并在体外和淀粉样蛋白沉积的小鼠模型中抑制 Abeta 纤维和低聚物的形成。在这里，我们研究了 CysC 对培养的原代海马神经元和暴露于寡聚体或纤维状细胞毒性 Abeta 形式的神经元细胞系的影响。与预形成的寡聚体或纤维状 Abeta 一起添加分泌的人 CysC 可增加细胞存活率。虽然 CysC 抑制 Abeta 聚集，但它不会溶解预先形成的 Abeta 纤维或低聚物。因此，CysC 通过防止形成有毒形式的 Abeta 以及直接保护神经元细胞免受 Abeta 毒性的侵害，在 AD 中具有多种保护作用。对 CysC 水平的治疗性操纵可导致高于生理水平的稍高浓度，从而可防止 AD 中的神经元细胞死亡。
