Sirt1调控tau蛋白O-GlcNAc糖基化在阿尔茨海默tau病理性改变中的新机制

Tau在AD患者脑中被异常过度磷酸化，形成神经纤维缠结（NFTs)。tau也被O-GlcNAc糖基化修饰，tau的O-GlcNAc糖基化对其磷酸化具有负调节作用。Tau的O-GlcNAc糖基化水平受到OGT和OGA的调节。Sirt1是与AD相关的去乙酰化酶，Sirt1对tau乙酰化修饰的影响已有报道，而其对tau的O-GlcNAc糖基化、磷酸化修饰的作用却鲜有研究。前期研究中我们首次发现在AD患者脑匀浆中Sirt1蛋白表达水平增高；预实验结果提示Sirt1可能通过调节OGT的表达而影响tau的O-GlcNAc糖基化，从而调控tau的磷酸化。本课题拟在分子、细胞、AD模型动物和AD患者脑组织，系统研究药物调控Sirt1对tau的O-GlcNAc糖基化、磷酸化的影响机制，为与tau翻译后修饰相关神经退行性疾病的防治提供分子依据。

Tau is abnormally hyperphosphorylated resulting in NFTs in the brains with AD. Tau is also posttranslational modified by O-GlcNAc. The O-GlcNAcylation of tau regulates the phosphorylation of tau negatively. The level of O-GlcNAcylation is controlled by the relative activities of OGT (O-GlcNAc transferase) and OGA (O-GlcNAcase). Sirt1 is an AD-associated deacetylase. The effect of Sirt1 on the acetylation of tau has been reported. Whether Sirt1 also affects the O-GlcNAcylation and phosphorylation of tau has not been determined. In the preliminary data, we have found for the first time that the protein level of Sirt1 was increased in brain homogenate of AD individuals. Preliminary data suggest that Sirt1 may regulate the O-GlcNAcylation of tau by modulating the expression of OGT and then influence the phosphorylation level of tau. The specific goal of this project is to investigate how the targeted adjustment of Sirt1 regulates the O-GlcNAcylation and phosphorylation of tau in vitro and in vivo. The proposed studies will provide significant new insights into the molecular mechanism of neurodegenerative disease related to the posttranslational modifications of tau.