SIRT1在糖尿病认知障碍中的作用及机制研究

SIRT1 is indispensable for normal learning and memory. Its activation benefits the brain from neurodegeneration. In the preliminary experiment for the application, we found that the SIRT1 expression was decreased in the hippocampus of STZ-induced diabetic mice. In previous research, we have documented that the over-activation of mTOR was involved in the development of diabetes-related cognitive dysfunction through increasing the hyperphosphorylation of tau. It was reported that SIRT1 could inhibit mTOR signaling and acetylate tau protein. It is unknown whether SIRT1 is involved in the development of diabetes-related cognitive dysfunction. In the present study, we plan to clarify the mechanism of tau hyperphosphorylation regulated by SIRT1. These proposed studies will open a new direction to develop novel drugs for diabetes-related cognitive dysfunction.

SIRT1是维持学习、记忆功能的关键调节子，激活SIRT1能逆转多种神经退行性疾病发生。我们预实验发现，STZ诱导的糖尿病小鼠成模4周后出现明显的认知障碍，且SIRT1在海马组织的表达随着病程的延长逐渐下降。我们前期研究证实，过度激活的mTOR促进tau蛋白异常磷酸化，并介导糖尿病认知障碍发生。SIRT1负性调控mTOR信号通路，亦可直接促进tau蛋白去乙酰化。SIRT1表达异常是否介导糖尿病认知障碍的发生与发展？尚未见相关报道。我们拟从tau蛋白合成、磷酸化、去磷酸化及降解四个层面揭示SIRT1调节tau蛋白异常磷酸化及糖尿病认知功能的机制。本项目有助于阐明糖尿病认知障碍的发病机制，为确立SIRT1作为防治糖尿病认知障碍的新靶点提供科学依据。

SIRT1是维持学习记忆功能的关键因子，激活SIRT1能逆转多种中枢神经退行性病变。本项探讨了SIRT1在糖尿病认知功能障碍中的作用及机制。研究结果显示：糖尿病小鼠海马组织mTOR信号通路过度激活，mTOR抑制剂雷帕霉素能明显抑制糖尿病海马组织tau蛋白的异常磷酸化及认知障碍；糖尿病小鼠海马组织SIRT1蛋白表达及活性明显降低；高糖抑制分化后SH-SY5Y神经细胞SIRT1蛋白的表达及活性；过表达SIRT1抑制高糖诱导的分化后SH-SY5Y神经细胞凋亡，并明显抑制mTOR信号通路及tau蛋白磷酸化水平。该研究证实，高糖是诱导糖尿病海马神经元SIRT1蛋白表达及活性下降的重要原因； SIRT1抑制mTOR信号通路从而调控tau蛋白过度磷酸化可能是其调节糖尿病认知功能的重要机制之一。