二苯乙烯苷对阿尔茨海默病tau蛋白异常磷酸化的干预机制

Alzheimer's disease (AD) pathogenesis is closely related to the excessive phosphorylation of tau protein. How to inhibit the excessive phosphorylation of tau protein is regarded as an efficient way of the treatment of AD. Our previous studies have confirmed Stilbene glucoside (TSG) has good resistance to dementia. Follow-up studies showed that TSG can obviously increase the cell survival rate of excessive phosphorylation cell model, significantly reduce the expression of p-tau (T205, S199) protein and GSK-3β , increase the expression of PP2A. It suggest that TSG can inhibit tau protein excessive phosphorylated by adjusting the tau protein kinase and protein phosphatase expression, but its mechanism remains to be further studied. To this end, we propose a hypothesis: TSG may through the intervention of tau protein phosphorylation and dephosphorylation, reduce excessive tau protein phosphorylation and achieve the goal of treatment of AD. To test this hypothesis, this project is designed to detect the intervention of TSG on protein kinase，protein phosphatase and their regulatory factors expression in APP/PS1/tau transgenic mice so as to evaluate the effect of TSG on tau protein phosphorylation and dephosphorylation. The interaction and relationship between tau protein kinase, protein phosphatase and their regulatory factors are investigated and try to provide the experimental basis for the development of drugs for AD.

阿尔茨海默病（AD）的发病机制与tau蛋白过度磷酸化密切相关。如何最大限度抑制tau蛋白过度磷酸化被认为是治疗AD的有效途径。课题组前期研究证实二苯乙烯苷（TSG）具有良好的抗痴呆作用。后续研究发现，TSG可明显增加过磷酸化细胞模型的细胞存活率，显著降低p-tau（T205、S199）位点的蛋白表达，降低GSK-3β和增加PP2A的表达，提示TSG可抑制Tau蛋白过度磷酸化，但其作用机制还有待进一步探讨。为此，我们提出假说：TSG可能通过干预tau蛋白的磷酸化和去磷酸化，减少tau蛋白过度磷酸化而达到治疗AD的目的。为了验证这一假说，我们拟采用高表达人类tau蛋白突变和性状的APP/PS1/tau三转基因小鼠为模型，进一步探讨TSG对tau蛋白磷酸化的蛋白激酶和去磷酸化的蛋白磷酸酶及其调控因子表达的干预作用，分析各种酶及其调控因子之间的相互作用和相关性，为开发AD早期干预药物提供实验依据。

阿尔茨海默病（AD）的发病机制与tau蛋白过度磷酸化密切相关。如何最大限度抑制tau蛋白过磷酸化被认为是治疗AD的有效途径。前期研究证实：二苯乙烯苷（TSG）具有良好的抗痴呆作用。在后续的研究中发现，TSG可明显增加过磷酸化细胞模型的细胞存活率，显著降低p-tau（T205、S199）位点的蛋白表达，降低GSK-3β和增加PP2A的表达，提示TSG可抑制Tau蛋白过度磷酸化，但其作用机制还有待进一步探讨。本项目是在前期研究基础上，以高表达人类tau蛋白突变和性状的APP/PS1/tau三转基因小鼠为模型，进一步探讨TSG对tau蛋白磷酸化的蛋白激酶和去磷酸化的蛋白磷酸酶及其调控因子表达的干预作用，分析各种酶及其调控因子之间的相互作用和相关性，为开发AD早期干预药物提供实验依据。项目的科研成果主要反映在发表或已录用的论文、培养的学术骨干及研究生上。