In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser^396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.

在阿尔茨海默氏病（AD）中，tau蛋白过度磷酸化会导致神经原纤维缠结，微管不稳定和神经变性。确定tau过度磷酸化的机制将提供对AD病理的更好理解。胱抑素C（CysC）是迟发性AD的危险因素，其水平在AD患者的大脑中被上调。CysC在AD发病中的作用尚不清楚。在这项研究中，我们发现3xTg-AD小鼠大脑中的CysC水平上调。我们证明CysC不会影响细胞Aβ的生产。然而，当在神经元（NGF分化的PC12细胞）中过表达时，CysC抑制GSK3β的更新，促进GSK3β催化的Ser ^396/404的tau磷酸化并导致微管不稳定。我们的数据为CysC在AD发病机理中的作用提供了新颖的见解。