TREM2-TLR4介导的神经炎症在糖尿病慢性脑低灌注认知功能障碍中的作用及机制

Diabetes mellitus can aggravate neuronal damage in chronic cerebral hypoperfusion, leading to cognitive dysfunction, but its mechanism remains unclear. Our previous study suggested that inflammatory response may promote the development of cognitive dysfunction in diabetic chronic cerebral hypoperfusion, accompanied by a marked upregulation of TREM2 expression in the hippocampus. TREM2 is a membrane receptor specifically expressed in the microglia of the central nervous system. It can regulate the release of inflammatory mediators, mediate the phagocytosis of microglia, and is associated with TLR4 mediated inflammatory response signaling pathway.Therefore, a hypothesis is proposed that TREM2 can alleviate the neuroinflammation by negatively regulating the TLR4 signaling pathway and thereby improve cognitive dysfunction of diabetic chronic cerebral hypoperfusion. Based on previous studies, we intend to use diabetic chronic cerebral hypoperfusion animal model and primary microglial cell culture, by knocking down and overexpressing TREM2, to study its role in diabetic chronic cerebral hypoperfusion injury. In combination with TLR4 receptor agonists, the mechanism of TREM2-TLR4-mediated neuroinflammation in cognitive impairment of diabetic chronic cerebral hypoperfusion is further analyzed. These results of our study will not only benefit for the understanding of the mechanisms of cognitive dysfunction in diabetic chronic cerebral hypoperfusion but also improve the target therapy and the clinical intervention for this disease.

糖尿病可加重慢性脑低灌注状态下神经元损伤，导致认知功能障碍，但其发生机制至今仍不清晰。申请人前期研究提示炎症反应可促进糖尿病慢性脑低灌注动物认知功能障碍的发生发展，伴随着海马区TREM2表达明显上调。TREM2为特异表达于中枢神经系统小胶质细胞的膜受体，可调节炎症介质的释放，介导小胶质细胞的吞噬作用，与TLR4介导的炎症反应信号通路相关联。基于此，我们提出以下假说：TREM2可通过负性调节TLR4信号通路，缓解神经炎症，从而改善糖尿病慢性脑低灌注认知功能障碍。本课题拟利用糖尿病慢性脑低灌注动物模型及原代小胶质细胞培养，通过敲低和过表达TREM2，研究其在糖尿病慢性脑低灌注损伤中的作用，并结合TLR4受体激动剂，进一步分析TREM2-TLR4介导的神经炎症在糖尿病慢性脑低灌注认知功能障碍中的作用机制。研究结果将丰富糖尿病慢性脑低灌注致认知功能障碍的发病机制，为研发靶向干预药物提供方向。

糖尿病可加重慢性脑低灌注状态下神经元损伤，导致认知功能障碍，但其发生机制至今仍不清晰。前期研究提示伴随着海马脑区TREM2表达明显上调，炎症反应促进糖尿病慢性脑低灌注动物认知功能障碍的发生发展，。TREM2为特异表达于中枢神经系统小胶质细胞的膜受体，可调节炎症介质的释放，介导小胶质细胞的吞噬作用，与TLR4介导的炎症反应信号通路相关联。基于此，我们提出以下研究课题：TREM2是否是通过负性调节TLR4信号通路，缓解神经炎症，进而改善糖尿病慢性脑低灌注认知功能障碍。本课题利用糖尿病慢性脑低灌注动物模型及构建bv2小胶质细胞体外模型，通过敲低和过表达TREM2，研究其在糖尿病慢性脑低灌注损伤中的作用，并进一步分析TREM2-TLR4介导的神经炎症在糖尿病慢性脑低灌注认知功能障碍中的作用机制。研究结果显示，糖尿病慢性脑低灌注模型海马脑区TREM2表达的升高，同时伴随有神经炎症加重，神经元损伤，并最终导致认知功能障碍。进一步研究发现，TREM2通过抑制p38 MAPK激活缓解神经炎症并最终改善认知障碍。除此之外，我们的研究显示，姜黄素通过调整TREM2与TLR4表达从而抑制LPS导致的bv2小胶质细胞激活。动物体内的研究显示，姜黄素通过抑制神经炎症、细胞凋亡和细胞焦亡来改善糖尿病慢性脑低灌注模型的认知障碍。除此之外，我们还研究了NAD以及穿心莲内酯对慢性脑低灌注导致神经炎症以及认知障碍的保护作用。研究结果将丰富糖尿病慢性脑低灌注致认知功能障碍的发病机制，为研发靶向干预药物提供方向。