Rho族蛋白在糖脂代障碍小鼠脑卒中后认知功能障碍中的作用

About 30%-56.6% of survivors would develop cognitive dysfunction after stroke, which indicates a great burden to both patient and the society. And there are no effective prevention or treatment strategies available. Our previous research showed that high-fat diet could induce hyperglycemia and hyperlipidemia in mice which resulted in aggravation of ischemic brain injury. Furthermore, those animals manifested significant fear memory impairment. Also, Rac1 and Cdc42 expression were significantly elevated in the hippocampus of high-fat diet fed mice before brain ischemia but manifested obvious reduction at 14d after non-hippocampus stroke as contrary to mice fed with regular diet. Adult neurogenesis was also impaired in high fat diet-fed animals after stroke. And research have shown that small Rho GTPase including Rac1 are highly involved in adult neurogenesis during learning activity. These results indicated a possible causal relationship between Rac1 changes and hippocampus neurogenesis after cerebral ischemia that may cause the cognitive dysfunction. The current project is aimed to explore the mechanism that modulate neurogenesis in animals with impaired glucose and lipid metabolism especially after cerebral ischemic injury. And to identify the role of small Rho GTPases in the post stroke memory deficits in these animal models. We will also use chemical, genetic and optogenetic techniques to modulate the expression and activity of Rho GTPases to promote the recovery of hippocampus neurogenesis after cerebral ischemia in mice with metabolic dysfunction. This project will provide new insights into and approaches for the prevention and treatment of post stroke cognitive dysfunction, especially in high risk patients with lipid and glucose metabolic disorders.

卒中存活患者中约30%~56.6%会发生卒中后认知功能障碍，为社会与家庭带来极大负担，目前仍无有效治疗手段。本项目前期研究发现糖脂代谢异常动物非海马区脑缺血损伤后远期残留学习记忆功能障碍，而代谢异常动物海马Rho族蛋白Rac1、Cdc42均表达增强，卒中后明显降低，且卒中后海马新生神经元数度显著降低，而Rho族蛋白被认为在成体神经发生中具有重要作用，提示糖脂代谢异常对Rho蛋白的影响所致神经发生障碍可能是其发生卒中后记忆功能障碍的原因。因此，本项目拟探索糖脂代谢异常状态下脑缺血损伤后海马神经发生障碍的内在机制，明确Rho族蛋白变化在其中的作用，并通过化学、遗传学、光遗传学等手段调控Rho族蛋白和上下游激酶活性，以保护糖脂代谢异常状态下脑损伤后海马神经发生功能，为临床预防高危患者卒中后认知功能障碍提供新的研究思路与治疗策略。

卒中存活患者中约30%~56.6%会发生卒中后认知功能障碍，为社会与家庭带来极大负担，目前仍无有效治疗手段。糖脂代谢异常是影响卒中后认知功能障碍的易感因素，海马神经发生是学习记忆的基础。本项目研究发现糖脂代谢异常促进小鼠空间记忆及情景相关恐惧记忆障碍，使小鼠海马Rac1、RhoA蛋白表达升高，体外培养的原代神经干细胞Rho族蛋白表达升高，干细胞增殖、迁移与分化能力降低。进一步研究发现糖脂代谢异常动物脑缺血损伤后远期残留学习记忆功能障碍，代谢异常动物海马Rho族蛋白Rac1、Cdc42均表达增强，卒中后明显降低，而RhoA卒中后14天显著升高。且卒中后海马新生神经元数量显著降低。Rho族蛋白抑制剂特异性抑制后可逆转糖脂代谢异常对神经干细胞增殖的抑制作用。在体光遗传学调控海马区Rac1表达可显著促进小鼠空间记忆能力。Rock特异性抑制剂，可显著逆转糖尿病小鼠的空间记忆功能障碍，可能是通过影响下游Rock1活性，影响突触后蛋白PSD95的合成与表达而引起的认知功能改变，Rock1可能是下游主要的效应因子。提示我们，卒中前后特异性调控糖尿病小鼠海马Rac1表达及活性或特异性抑制RhoA，逆转神经干细胞的增殖、迁移与分化的抑制，同时通过抑制下游Rock1促进PSD95的表达，及改善神经元突触可塑性，进而改善糖尿病小鼠的认知功能障碍。另一方面，我们发现糖尿病db/db小鼠表现出脑血管重构、PPAR-γ抑制和大脑特别是神经元炎症增强，致使db/db小鼠脑缺血再灌注损伤增强。通过简单的早期吡格列酮处理，我们成功地控制了db/db小鼠的血糖升高，抑制了脑血管重构，逆转了PPARγ抑制和慢性脑炎症，抑制了db/db小鼠脑缺血性损伤及神经功能恶化。

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