microRNA-99a调节tau蛋白磷酸化在抑制糖尿病海马神经细胞退行性变中的作用及机制研究

Degeneration of hippocampal neurons in diabetes mellitus (DM) was induced by hyperphosphorylated tau. However, the mechanisms of tau hyperphosphorylation in DM are not exactly known. In the preliminary experiment for the application, we found that the miR-99a expression was decreased in the hippocampus of diabetic rats and miR-99a inhibited tau phosphorylation and neurodegeneration induced by high dosage of glucose in cultured hippocampal neurons. Based on the fact that mTOR/p70S6K pathway mediates the phosphorylation and translation of tau protein, we speculated that the down-regulation of miR-99a enhanced the phosphorylation of tau and neurodegeneration of hippocampus in diabetic rats through increasing the expression of mTOR. In the present study, we plan to confirm the role of miR-99a in diabetes-related degeneration of hippocampal neurons. And clarify the mechanism of miR-99a-mediated tau hyperphosphorylation and neurodegeneration through mTOR/p70S6K signaling pathway. The project is beneficial to clarifying the mechanism of diabetes-related degeneration of hippocampal neurons and will provide a new target for pharmacological therapy in cognitive dysfunction of diabetes mellitus.

tau蛋白过度磷酸化诱导糖尿病海马神经细胞退行性变，然而糖尿病海马组织tau蛋白过度磷酸化的机制尚未完全阐明。我们预实验发现：糖尿病大鼠海马组织miR-99a表达随病程的延长逐渐降低；miR-99a mimic能明显抑制高糖诱导的海马神经细胞tau蛋白磷酸化及退行性变。基于mTOR/p70S6K信号通路调控tau蛋白磷酸化与合成，我们推测：糖尿病时海马组织下调的miR-99a对mTOR表达的抑制作用减弱，使得p70S6K活性增强，从而促进tau蛋白的过度磷酸化，进而介导糖尿病海马神经细胞退行性变的发生。本项目拟将动物与细胞实验相结合，在确认miR-99a调节糖尿病海马神经细胞退行性变的基础上，深入探讨miR-99a抑制tau蛋白过度磷酸化及海马神经细胞退行性变的机制是否涉及mTOR/p70S6K途径。该研究有助于阐明糖尿病海马神经细胞退行性变的发病机制，为防治糖尿病认知障碍提供新思路。

tau蛋白过度磷酸化可导致海马神经细胞发生退行性变。众多研究表明miRNA可调控tau蛋白的神经毒性。本项目拟探讨miR-99a抑制tau蛋白过度磷酸化及海马神经细胞退行性变的机制是否涉及mTOR途径。我们的结果显示：①糖尿病海马组织中miR-99a表达下调与糖尿病海马神经细胞退行性变及认知功能障碍相关；②高糖能明显诱导降低海马神经细胞miR-99a的表达，且miR-99a能逆转高糖诱导的海马神经细胞发生退行性变；③miR-99a通过靶向mTOR抑制tau蛋白的过度磷酸化；④糖尿病认知功能障碍发生过程中，海马组织miR-99a表达的下调可能减弱了其对tau蛋白过度磷酸化的抑制作用，从而导致海马神经细胞退行性变及认知功能障碍。该研究证实，高糖是诱导糖尿病海马神经元miR-99a表达下调的重要原因之一；miR-99a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。