阿尔茨海默病 (Alzheimer’s disease，AD) 患者脑内神经原纤维缠结的主要成分是异常过度磷酸化的Tau蛋白。前期工作中我们在AD患者脑组织内发现C1q蛋白与神经原纤维缠结存在着共定位，在体外实验中进一步证实过表达C1q可以显著增加SH-SY5Y细胞内Tau蛋白的磷酸化水平。因此我们推测：C1q蛋白很可能通过一系列级联反应而促进神经元内Tau蛋白的过度磷酸化，增加神经原纤维缠结的形成数量，进而在AD的发病中起重要作用。本研究拟在前期工作基础上建立敲除c1q基因的Tau转基因小鼠模型（Tau+/C1q-/-），从分子水平、整体水平探讨C1q蛋白对Tau蛋白磷酸化、神经胶质细胞增生及神经元突触丢失的影响，明确C1q蛋白表达缺失对MAPT基因P301S突变 (Tau+) 转基因小鼠学习与记忆能力、运动能力等行为学的影响，并探索C1q蛋白影响Tau蛋白磷酸化及一系列改变的分子机制。

The neurofibrillary tangles in AD brain are comprised of abnormally hyperphosphorylated tau. In our previous study, we revealed a high degree of co-localization of neurofibrillary tangles with C1q and its downstream components in AD brain. We also showed that overexpression of C1q in SH-SY5Y cells significantly increased tau phosphorylation in vitro. Our hypothesis is that C1q promotes hyperphosphorylation of Tau in neurons through a series of cascades and increases the number of neurofibrillary tangles, and thereby plays an important role in the pathogenesis of AD. Based on these results, we will generate a genetic deficiency of C1q in Tau transgenic mouse model（Tau+/C1q-/-）. Then we are going to explore c1q’s effects on Tau phosphorylation, glial cell activation and synapse loss in vivo, and investigate whether genetic deletion of C1q could affect behavioral deficits such as learning and memory abilities and motor skills in Tau+ mice. Furthermore, we will try to identify the molecular mechanisms of C1q’s effect on Tau protein phosphorylation and a series of changes.