阿尔茨海默病p75NTR对Tau蛋白过度磷酸化的调控作用和机制研究

Aβ和Tau蛋白过磷酸化是AD发生的关键事件，Tau是Aβ毒性作用的重要下游分子，Aβ诱导Tau蛋白过磷酸化，但其受体通路不清楚。我们发现：p75NTR是调控Aβ神经毒性作用的关键受体；敲除p75NTR基因的AD小鼠脑内Tau蛋白过磷酸化程度减轻；阻断p75NTR可减轻Aβ诱导的SH-SY5Y细胞Tau蛋白过磷酸化。表明p75NTR很可能是介导Aβ诱导Tau蛋白过磷酸化的重要受体。本研究拟首先从离体水平探讨p75NTR对Aβ诱导Tau蛋白过磷酸化的作用及机制；再制作敲除p75NTR基因的含Tau突变基因和AAP基因的小鼠，从在体水平研究p75NTR对Aβ诱导Tau蛋白过磷酸化的作用和机制；最后，通过脑内病毒转染过表达p75NTR胞外段阻断Aβ与p75NTR结合，观察对AD样病理和行为障碍的改善作用。本项目对揭示Aβ诱导Tau蛋白过磷酸化的关键受体途径，建立AD防治新方法，具有重要意义。

Aβ accumulation and tau hyperphosphorylation are key events in the pathogenesis of AD. Tau is an important downstream mediator of Aβ toxicity. Aβ induces tau hyperphosphorylation. But the pathways linking Aβ and tau are not clearly understood. We found that p75NTR is a crucial receptor for Aβ neurotoxicity, tau phosphorylation is reduced significantly in the brain of p75NTR gene knockout APPswe/PS1dE9 mice and inhibition of p75NTR reduced tau hyperphosphorylation induced by Aβ in SH-SY5Y cells. These results show that p75NTR maybe an important receptor signaling pathway which mediates tau hyperphosphorylation induced by Aβ. In the present study, we will investigate the role of p75NTR on tau hyperphosphorylation induced by Aβ and the underlying mechanisms via generation of new mouse model which expresses human mutation tau gene and APP gene with p75NTR gene knockout. And we will study whether p75NTR-ECD improves the AD-like pathology and behaviour disorders, and blocks Aβ binding to p75NTR via AAV viral transfection in the hippocampus of AD mice . This work suggests that p75NTR is a potential therapeutic target for AD with a great value for the effective drug development.