小胶质细胞P2Y12受体在脑白质缺血后髓鞘损伤中的作用机制

White matter ischemic disease (WMI) is one of major pathogenic factors of vascular cognitive impairment. Oligodendrocyte death and subsequent demyelination contribute to vascular cognitive impairment. The process of myelin loss is accompanied with microgliosis after white matter ischemia. Microglia activation can induce microenvironment change of myelin regeneration. P2Y12 receptor is a specific receptor of microglia in CNS, and has a crucial role in microglia motility, activation, and inflammation. In the present study, we found that STAT3/SOCS3 pathway might be involved in P2Y12–mediated microglial activation and production of inflammatory cytokine. Based on these, we speculate that microglial activation and P2Y12 up-regulation mediate myelin damage and neural circuit injury, provide a detrimental microenvironment for myelin regeneration, and eventually contribute to cognitive decline. We will target microglia P2Y12 receptor and investigate the role and possible mechanisms of microglia in WMI, which will provide a novel therapeutic thought for myelin loss and cognitive decline after WMI.

脑白质缺血性病变(WMI)是介导血管性认知功能障碍的重要因素。少突胶质细胞损伤引起的髓鞘脱失是导致WMI后神经功能环路受损、继而出现认知功能障碍的重要机制。白质受损后小胶质细胞(MG)的活化往往与神经元轴突和髓鞘损伤伴随而存。WMI后炎性微环境是影响髓鞘再生的重要障碍。P2Y12受体是中枢MG特异性受体，介导MG活化、运动, 并与CNS炎症反应密切相关。前期工作证实，STAT3/SOCS3信号通路可能参与了WMI后P2Y12受体介导的MG激活和炎症因子的产生。我们推测：WMI后MG激活以及P2Y12受体的异常活化，可介导髓鞘损伤和神经环路受损，提供不利于髓鞘再生的微环境，最终导致认知功能障碍。本项目拟以小胶质细胞消融、基因敲除、双光子成像和膜片钳等为技术手段，以MG特异性P2Y12受体为调控靶点，探讨MG在WMI中的作用及其可能机制，为WMI后髓鞘损伤修复和认知障碍的治疗提供新思路。

本项目以临床常见的脑白质损害为研究切入点，以小胶质细胞特异性P2Y12受体为调控靶点，通过调节小胶质细胞的活性和功能，探讨小胶质细胞以及P2Y12受体在脑白质缺血病变中的作用及其可能机制。收集临床WML患者病例，观察了WML患者脑白质病变的多模态影像学变化与认知功能障碍的相关性，发现WML伴有MCI组FA值明显降低，MD值明显增高，说明脑白质缺血伴认知障碍患者髓鞘破坏明显。建立了小鼠慢性低灌注脑白质损伤BCAS模型，发现慢性低灌注后，小胶质细胞明显活化且数目增多，少突胶质前体细胞数量增多而分化成熟的少突胶质细胞数量减少。利用P2Y12-/-基因鼠探讨了P2Y12敲除对BCAS后小胶质细胞分型及少突胶质细胞前体细胞增殖分化的影响，发现P2Y12敲除能促进损伤后M2型小胶质细胞的表达，并可降低成熟少突胶质细胞数量的减少程度,促进少突胶质细胞向成熟少突胶质细胞的分化，从而发挥保护作用，减轻白质缺血后髓鞘损伤及认知功能障碍。本研究结果为WMI后髓鞘损伤修复和认知障碍的治疗提供了新思路。