由过度磷酸化Tau形成的成对螺旋丝组成的神经元纤维缠结是许多Tau蛋白病共同具有的病理特征。但目前还不清楚补体C3/C3aR过度活化是否参与了Tau蛋白过度磷酸化介导的神经退行性疾病过程。我们前期研究发现，补体C3及C3a的受体C3aR在Tau P301S转基因鼠的脑内表达显著上调，而C3基因敲除能明显减少该模型Tau蛋白磷酸化。因此我们推测补体C3/C3aR的过度活化参与Tau蛋白过度磷酸化的病理过程，在Tau蛋白病的认知功能障碍发生中起着重要的作用。本项目拟在已有基础上，利用Tau+/C3-/-双转基因小鼠模型以及C3aR拮抗剂干预，采用免疫印迹、电镜、离体海马脑片场电位记录及行为学等方法探讨C3敲除或C3aR拮抗剂干预是否可以抑制Tau蛋白磷酸化进而发挥对Tau蛋白病的保护作用及可能机制，以阐明C3/C3aR能否作为Tau蛋白病防治的新靶标，为AD以及Tau蛋白病的治疗提供新的思路。

Tau is abnormally hyperphosphorylated by several kinases and eventually aggregates to form intraneuronal neurofibrillary angles, a common pathological hallmark in a variety of neurodegenerative Tauopathies including Alzheimer's disease (AD), Pick's disease, progressive supra- nuclear palsy, corticobasal degeneration and Parkinsonism linked to chromosome 17. But the contribution of activation of complement protein 3 (C3) or C3a receptor to Tau-mediated neurodegenerative is not clear. Previously we provided evidence that expression of C3 and C3aR were significantly increased in of Tau P301S transgenic mice compared with wild-type C57BL/6J mice, Tau+/c3-/- mice develops less Tau hyperphosphorylation compared with Tau P301S transgenic mice. Considering these and other studies our overall hypothesis is that activation of complement protein 3 (C3) or C3a receptor contributes to Tau hyperphosphorylation and plays a detrimental effect on cognitive dysfunction in Tauopathies. This proposal will test this hypothesis using western blot, histochemical , electron microscopy of synapse, electrophysiology and other approaches to observe whether C3-/- and C3aR antagonist intervention produce protective effects on the Tau hyperphosphorylation and synapse and cognitive dysfunction in Tauopathies. These experiments will address whether manipulating the C3/C3aR is a new target for Taupathies. These studies may reveal new insights into innovative therapeutic avenues for Tauopathies especially for AD .