补体C3b激活小胶质细胞介导的突触丢失在糖尿病认知减退中的作用及机制研究

海马突触丢失是糖尿病认知减退的重要病理特征。近年研究提示，小胶质细胞过度吞噬突触导致突触丢失，引发神经退行性疾病。糖尿病是慢性炎症性疾病，存在补体系统紊乱，而补体是调控小胶质细胞吞噬突触的关键信号，但其是否参与糖尿病突触丢失及驱动机制尚不明确。我们前期通过高通量测序发现糖尿病小鼠海马脑区补体C3b表达升高，小胶质细胞吞噬功能增强，神经突触密度下降；予小鼠海马注射C3b蛋白导致突触丢失增加。有意义的是，我们发现糖尿病患者认知减退，脑脊液中补体C3b升高。我们据此假设：补体C3b激活小胶质细胞吞噬突触，导致糖尿病突触丢失和认知减退。本研究拟利用C3b受体条件性敲除小鼠，脑立体定位注射等技术，明确小胶质细胞吞噬突触在糖尿病认知减退中的作用，阐明C3b激活小胶质细胞导致糖尿病突触丢失的具体机制，探讨干预C3b信号能否缓解糖尿病突触丢失。研究结果将阐明糖尿病认知减退发生的新机制，探寻可能的干预靶标。

The hippocampal synaptic loss is a well-documented pathological manifestation of cognitive decline in diabetes. Recently, it has been demonstrated that microglia excessively engulf synapses and lead to synaptic loss and neurodegenerative diseases. Diabetes is a chronic inflammatory disease with disorders in the complement system. Complement molecules are the key signals to regulate the synaptic engulfment by microglia. However, whether they participate in the synaptic loss of diabetes and their triggering mechanisms are poorly understood. Our preliminary results using high-throughput sequencing showed the increased expression of complement C3b, the enhanced phagocytosis of microglia, and the decreased synaptic density in the hippocampus of mice. Moreover, the injection of C3b protein into the hippocampus of mice resulted in more serious synaptic loss. Significantly, we further discovered cognitive decline in patients with diabetes and increased C3b in their cerebrospinal fluid. Accordingly, we hypothesis that the complement C3b-mediated synaptic engulfment by microglia is implicated in the synaptic loss and cognitive decline of diabetes. This study intends to use the C3b receptor conditional knockout mice and techniques including stereotactic injection in the brain, aiming at: investigating the role of the synaptic engulfment by microglia in cognitive decline of diabetes, clarifying the underlying mechanism of C3b-induced microglia activation and synaptic loss in diabetes, and determining whether the intervention of C3b signal can alleviate synaptic loss in diabetes. The findings will shed light on the novel mechanism and potential therapeutic targets of cognitive decline in diabetes.