运动与阿尔茨海默病：基于Tau蛋白翻译后修饰视角的研究述评

阿尔茨海默病（Alzheimer’s disease，AD）是一种与年龄有关的神经退行性疾病，严重危害老年人的身心健康，给社会带来巨大的经济压力。但目前其发病机制尚不完全明确，临床仍无根治的有效方法。Tau蛋白是一种微管相关蛋白质，能够参与维持微管相关结构稳定，具有可溶性且不会聚集。在AD病理状态下，病人脑内Tau蛋白结构和功能异常。异常的Tau蛋白聚集成不可溶的神经纤维缠结，损害微管运输能力，导致病人认知功能障碍。Tau蛋白结构和功能的改变是由多种翻译后修饰过程来调控的，即将特定的化学修饰基团与Tau蛋白N-端或C-端结合，直接改变蛋白质的性质和功能。AD病人脑内Tau蛋白的磷酸化、糖基化、乙酰化及SUMO化等多种翻译后修饰异常，与Tau蛋白的降解和毒性物质的聚集密切相关。本文综述近年来的研究后发现，运动可以通过改善Tau蛋白翻译后的某些异常修饰来预防和改善AD，主要作用方式如下：(1）运动可通过抑制GSK 3β和MAPK等蛋白激酶活性来抑制Tau蛋白的过度磷酸化，可能通过上调PP2A活性来促进Tau蛋白去磷酸化；(2）运动可通过提高GLUT1和GLUT3蛋白质水平，可能通过调节OGA和OGT活性平衡，提高蛋白质O-GlcNAc糖基化水平；(3）运动可能通过AMPK/mTORC1途径抑制p300以及激活SIRT1，降低Tau蛋白乙酰化水平；同时运动还可能通过抑制HDAC6，改善Tau蛋白KXGS基序异常乙酰化程度；(4）运动可能通过调节磷酸化与SUMO化共定位点，改善Tau蛋白异常SUMO化水平。

Exercise and Alzheimer’s Disease: A Review of Research Based onPost-translational Modification of Tau Protein

Alzheimer’s disease (AD) is an age-related neurodegenerative disease which seriously damages the physical and mental health of the elderly and causes huge economic pressure to the society. However, the pathogenesis of AD is not completely elucidated. There is still no effective drug to cure AD in clinical practice. Tau protein is a soluble and non-aggregating microtubule-related protein, which can stabilize microtubule structure. The structure and function of Tau protein are abnormal in AD’s brain while under pathological conditions, and the abnormal Tau protein aggregates to insoluble neurofibrillary tangles which damages microtubules and leads to cognitive dysfunction. These changes of Tau protein are regulated by a variety of post translational modifications, which directly change the properties and functions of proteins by attaching specific chemical moieties to Tau protein’s C-terminus or N-terminus. It’s confirmed that a variety of Tau post-translational modifications, like phosphorylation, glycosylation, acetylation and sumoylation is abnormal in AD’s brain, which is closely related to Tau degradation and the accumulation of toxic substances. In this review, we summarized the latest progress supporting the role of exercise regulated Tau post-translational modification in the prevention and treatment of Alzheimer’s disease． Firstly, exercise inhibits tau protein hyperphosphorylation by suppressing the activity of GSK-3β and MAPKs and possibly by up-regulating the activity of PP2A. Secondly, exercise increases tau protein O-GlcNAcylation by up-regulating the expression of GLUT1 and GLUT3, also possibly by regulating the balance of activity of OGT and OGA. Thirdly, exercise decreases tau protein acetylation possibly by inhibiting p300 and activating SIRT1; exercise regulates the acetylation of Tau KXGS possibly by inhibiting HDAC6. Lastly, exercise inhibits abnormal Tau sumoylation possibly by regulating the co-location sites of phosphorylation and sumoylation.