饥饿对小鼠脑中tau蛋白磷酸化和O-GlcNAc糖基化的影响

Fasting Induces Decreased O-GlcNAcylation and Increased Phosphorylation of tau in Mouse Brains

为了探讨大脑中葡萄糖摄取和代谢障碍在阿尔茨海默病(Alzheimer$sdisease,AD)神经退行性病变中的作用,将昆明种小鼠进行饥饿和再喂食处理,并使用多种磷酸化tau蛋白特异性的抗体和蛋白O-GlcNAc糖基化特异性抗体进行检测,观察饥饿及恢复喂养后不同时间点大脑皮质中tau蛋白糖基化及多个位点磷酸化的变化.结果显示:饥饿处理引起小鼠大脑皮质中总蛋白和tau蛋白的O-GlcNAc糖基化水平降低,同时tau蛋白磷酸化水平升高,饥饿引起的tauO-GlcNAc糖基化和磷酸化改变均在恢复进食后逆转成正常水平.该研究结果提示:大脑中tau蛋白的磷酸化和O-GlcNAc糖基化之间存在相互调节,脑中葡萄糖代谢障碍可能通过下调tau蛋白O-GlcNAc糖基化水平使tau蛋白产生异常过度磷酸化,进而促发AD的病理进程.这一结果为在早期阶段通过逆转tau蛋白异常过度磷酸化治疗AD成为可能提供了实验基础.

To explore the role of impaired brain glucose uptake/metabolism in neurodegeneration of Alzheimer＇s disease （AD）, the relationship between an impaired brain glucose uptake/metabolism （down-regulation of tau O-GlcNAcylation） and the abnormal hyperphosphorylation of tau was investigated in fasting mice. It was found that fasting caused reduction of tau O-GlcNAcylation and a concomitant increase of tau phosphorylation at several hyperphosphorylation sites as seen in AD brain. Furthermore, hyperphosphorylation of tau induced by fasting was reversible in the brain after re-feeding. These findings provide a novel mechanism explaining how impaired brain glucose uptake/metabolism may contribute to AD-like tau hyperphosphorylation and also suggest feasibility to treat AD by reversing abnormal hyperphosphorylation of tau at early stages of the disease.