p75NTR在阿尔茨海默病tau蛋白病变扩散中的作用和机制研究

Tau蛋白过度磷酸化引起的神经原纤维缠结是阿尔茨海默病（AD）的主要病理特征之一，AD脑内tau蛋白病变扩散对AD发展起重要作用，其分子机制不清楚。我们发现p75NTR与tau蛋白相互结合、敲除p75NTR基因小鼠脑内tau蛋白病变扩散减少。而AD脑内tau蛋白病变扩散与p75NTR阳性神经元纤维投射分布一致。我们提出，p75NTR很可能是介导tau蛋白病变扩散的关键受体途径。拟采用表达或敲除p75NTR基因，检测tau蛋白磷酸化、NFTs的改善，探讨p75NTR在tau蛋白扩散中的作用；采用免疫共沉淀、FRET技术、IAsys分析系统检测tau与p75NTR特异性结合，采用激光共聚焦活细胞成像等技术检测p75NTR介导tau蛋白的内吞作用；采用计算机模拟p75NTR的tau结合部位，探讨转染表达p75NTR结合部位突变基因对防治AD的作用。本项目对揭示AD发生机制及AD防治具有重要意义。

Abnormal hyperphosphorylation of tau is a key factor in Alzheimer’s disease. The newly discovered shows trans-synaptic spread of tau pathology, however, the underlying mechanisms are still unclear. We found that p75NTR and tau could bind directly to each other and spreading of tau pathology reduced in the p75NTR knockout mouse brain. The reported showed that the field of tauopathy proganation is consistent with p75NTR positive neurons fiber projection area in Alzheimer's disease brain. We hypothesise that p75NTR may play an important role in trans-synaptic spread of tau pathology. In order to investigate the effect of p75NTR on tauopathy proganation, distribution and the levels of tau including total tau, phosphorylated tau and neurofibrillary tangles in cells will be detected at the presence or absence of p75NTR in vivo and in vitro including cell culture, primary neuron culture. To explore the underlying mechanisms, co-immunoprecipitation, FRET, SNAP-Tag, IAsys system will be applied to detect the relation of p75NTR combined with tau. To investigate the role of p75NTR mediated tau endocytosis, electron microscopy and Laser confocal live cell imaging system will be applied. And computer simulation of the molecules will be used to analyze the field combined with tau on p75NTR. Dot mutation and gene transfection expression will be used to verifythe effect of p75NTR in the process of tau endocytosis. Here, we are about to reveal the mechanism of tauopathy proganation, which will be important for blocking spread of tau pathology in Alzheimer's disease.