Tau蛋白过度磷酸化机制及其在阿尔茨海默病神经元变性中的作用

Molecular Mechanisms Underlie Alzheimer-like Tau Hyperphosphorylation and Neurodegeneration

Tau蛋白是神经元中含量最高的微管相关蛋白,其经典生物学功能是促进微管组装和维持微管的稳定性.在阿尔茨海默病(Alzheimer's disease,AD)患者,异常过度磷酸化的Tau蛋白以配对螺旋丝结构形成神经原纤维缠结并在神经元内聚积.大量研究提示,Tau蛋白异常在AD患者神经变性和学习记忆障碍的发生发展中起重要作用.本课题组对Tau蛋白异常磷酸化的机制及其对细胞的影响进行了系列研究,发现Tau蛋白表达和磷酸化具有调节细胞生存命运的新功能,并由此对AD神经细胞变性的本质提出了新见解.本文主要综述作者实验室有关Tau蛋白的部分研究结果.

Tau is the most abundant microtubule associated protein. The normal function of Tau is to promote microtubule assembly and stabilize microtubules. In Alzheimer＇s disease, Tau is abnormally hyperphosphorylated and the hyperphosphorylated Tau accumulates, in the form of paired helical filaments （PHF）, in the neuron to form neurofibrillary tangles. Numerous studies indicate that the abnormal Tau modifications play a crucial role in AD neurodegeneration and the cognitive deficits. We have studied systemically the mechanisms underlie Tau hyperphosphorylation and the effects of Tau phosphorylation on cell viability. We found unexpectedly that expression of the hyperphosphorylated Tau, at certain point, renders the cells more resistant to the exogenously induced cell apoptosis, whereas dephosphorylation of Tau promotes cell apoptosis. We also found that persistent Tau hyperphosphorylation and the cellular accumulation damage the neural functions and thus decrease the viability. Based on these findings, we propose that Tau hyperphosphorylation may play a dual role in leading the neurons to abort from an acute apoptosis and at the same time triggering a chronic neurodegeneration, which may explain why the degenerated neurons observed in the postmortem Alzheimer＇s brain are enriched with the hyperphosphorylated Tau proteins/tangles. It is suggested that proper intervention of Tau hyperphosphorylation may serve as a promising strategy in rescuing cell apoptosis and arresting neurodegeneration in Alzheimefs disease.