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 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.

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。一方面我们发现SIRT1通过CREB调节OGT的表达：实验结果显示SIRT1与CREB之间有相互作用，且SIRT1可以对CREB进行去乙酰化作用，SIRT1对OGT基因的转录调节依赖于其去乙酰化酶的活性；另一方面，我们发现SIRT1通过C/EBPα调节OGA的表达：实验结果显示SIRT1与C/EBPα之间有相互作用，且SIRT1可以对C/EBPα进行去乙酰化作用， C/EBPα抑制OGA的表达，而SIRT1通过抑制C/EBPα的表达而促进OGA的表达水平。在上述研究基础上，我们发现SIRT1明显地抑制tau蛋白的O-GlcNAc糖基化，同时，tau蛋白的磷酸化水平呈现位点特异性改变。中枢神经系统特异敲除SIRT1的小鼠（SIRT1条件敲除小鼠）呈现突触棘形态、密度以及突触可塑性的改变，SIRT1条件敲除小鼠学习记忆能力显著下降。我们发现AD患者脑中SIRT1蛋白表达降低的同时OGA蛋白水平也相应降低。我们的研究为以SIRT1和tau作为治疗靶点的AD药物开发利用提供新思路、开辟新途径。