GLP-1防治糖尿病认知障碍新机制--FOXO途径介导的代谢记忆清除

In recent years, advanced glycation end products / receptor for advanced glycation end products / reactive oxygen species (AGEs / RAGE / ROS) signaling axis - mediated metabolic memory is considered to be a risk factor for diabetes-related cognitive dysfunction, and the forkhead box class O (FOXO) transcription factor is involved in the formation of metabolic memory. In our previous study, we have found the amelioration effect of neurodegenerative changes in rat models of diabetes-related cognitive dysfunction by glucagon-like peptide-1 (GLP-1) receptor agonist, and GLP-1 can protect neurons against cytotoxicity induced by high glucose, AGEs or ROS. These results suggested that the effect of GLP-1 in metabolic memory may be a key aspect involved in the prevention and treatment of diabetes-related cognitive dysfunction by GLP-1, but the mechanism is unclear. In this project, first we will observe the effect of GLP-1 in metabolic memory, and explore the effect and mechanism of regulation of AGEs / RAGE / ROS signaling system by GLP-1; then we will intervene FOXO by using the transfection, RNA interference (RNAi) technologies and so on to investigate the role of FOXO activation / inactivation in metabolic memory and the regulation effect of GLP-1, and we will clarify the roles of protein kinase B (Akt), sirtuin 1 (SIRT1) pathways in the regulation of FOXO by GLP-1 receptor agonist. The aim of this project is to provide new experimental evidence for the potential targets of GLP-1 receptor agonist treatment of diabetes-related cognitive dysfunction.

近年来高级糖基化终产物/糖基化终产物受体/活性氧簇（AGEs/RAGE/ROS）信号轴介导的代谢记忆发生作为糖尿病并发认知障碍病因之一倍受关注，转录因子FOXO参与代谢记忆的形成。本课题组前期研究发现胰高血糖素样肽-1（GLP-1）可有效防治大鼠糖尿病相关中枢神经系统损伤，并能促使神经元抵抗高糖、AGEs及ROS所造成的细胞毒性，提示GLP-1对代谢记忆的清除可能是其防治糖尿病认知障碍的关键环节，但其具体作用及途径亟待进一步阐明。本项目首先观察GLP-1清除代谢记忆发生的作用，并探讨GLP-1对AGEs/RAGE/ROS信号系统的调控作用及机制；进一步采用转染、RNAi等技术考察FOXO在GLP-1清除代谢记忆中的作用及GLP-1对其具体调控机制，同时分析Akt、SIRT1途径在GLP-1受体介导的FOXO活性调控机制中的作用。为GLP-1防治糖尿病认知障碍提供新的研究思路及实验依据。

代谢记忆发生可能是导致糖尿病认知障碍关键因素之一，有研究发现转录因子Foxo参与代谢记忆的形成。项目前期研究发现胰高血糖素样肽-1（GLP-1）能缓解大鼠糖尿病相关中枢神经系统损伤，并促使神经元抵抗高糖、AGEs、ROS所造成的细胞毒性，提示GLP-1对代谢记忆的清除可能是其防治糖尿病认知障碍的关键环节，本项目旨在进一步阐明GLP-1受体激动剂清除代谢记忆防治糖尿病认知障碍的具体作用及途径。本研究建立了高糖代谢记忆及AGEs致神经元损伤细胞模型，GLP-1及其长效类似物exendin-4干预结果显示GLP-1受体激动剂对高糖代谢记忆及AGEs所致神经细胞损伤具有保护作用；分别基于II型糖尿病小鼠B6.BKS(D)-Leprdb/JNju和AGEs诱导建立代谢记忆及其相关的动物模型，明确GLP-1受体激动剂可改善模型动物认知水平及神经元损伤；同时，基于所建立的动物/细胞模型发现GLP-1受体激动剂可缓解代谢记忆相关因素AGEs导致的神经细胞凋亡及ROS异常，且GLP-1受体激动剂可通过影响NF-κB抑制AGEs诱导的RAGE表达异常；进一步，RNAi等确证了在GLP-1作用于代谢记忆过程中Foxo的地位，且GLP-1受体激动剂通过AKT及Sirt1途径调节Foxo磷酸化/乙酰化/核转位等异常，从而发挥相关活性。本项目深入探讨GLP-1受体激动剂改善代谢记忆防治糖尿病认知障碍的分子机制，为糖尿病认知障碍药物及靶标研究提供了新的思路及实验依据。通过本项目，已发表论文5篇（SCI论文4篇），参加国内外会议交流3次，协助培养研究生5名。