Department of Neurology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Institute of Geriatrics, Guangdong Institute of Neurosciences, Guangzhou 510080, China.
Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec H4H 1R3, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H4H 1R3, Canada.
Mol Cell Neurosci. 2018 Jun;89:1-8. doi: 10.1016/j.mcn.2018.03.009. Epub 2018 Mar 22.
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 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis.
在阿尔茨海默病（AD）中，tau 蛋白过度磷酸化导致神经原纤维缠结形成、微管不稳定和神经退行性变。确定 tau 过度磷酸化的机制将更好地了解 AD 的发病机制。半胱氨酸蛋白酶抑制剂 C（CysC）是晚发性 AD 的危险因素，其水平在 AD 患者的大脑中上调。CysC 在 AD 发病机制中的作用尚不清楚。在这项研究中，我们发现 CysC 水平在 3xTg-AD 小鼠大脑中上调。我们证明 CysC 不会影响细胞 Aβ 的产生。然而，当在神经元（NGF 分化的 PC12 细胞）中过表达时，CysC 抑制 GSK3β 的周转率，促进 GSK3β 催化的 tau 丝氨酸磷酸化，并导致微管不稳定。我们的数据为 CysC 在 AD 发病机制中的作用提供了新的见解。
