Kang Eun-Bum, Cho Joon-Yong
Exercise Biochemistry Laboratory, Korea National Sport University, Seoul, Republic of Korea.
J Exerc Nutrition Biochem. 2015 Sep;19(3):199-209. doi: 10.5717/jenb.2015.15090806. Epub 2015 Sep 30.
Neurofibrillary tangles, one of pathological features of Alzheimer's disease, are produced by the hyperphosphorylation and aggregation of tau protein. This study aimed to investigate the effects of treadmill exercise on PI3K/AKT/mTOR signal transmission, autophagy, and cognitive ability that are involved in the hyperphosphorylation and aggregation of tau protein.
Experimental animals (NSE/htau23 mice) were divided into non-transgenic control group (Non-Tg-Control; CON; n = 7), transgenic control group (Tg-CON; n = 7), and transgenic exercise group (Tg-Treadmill Exercise; TE; n = 7). The Tg-TE group was subjected to treadmill exercise for 12 weeks. After the treadmill exercise was completed, the cognitive ability was determined by conducting underwater maze tests. Western blot was conducted to determine the phosphorylation status of PI3K/AKT/mTOR proteins and autophagy-related proteins (Beclin-1, p62, LC3-B); hyperphosphorylation and aggregation of tau protein (Ser199/202, Ser404, Thr231, PHF-1); and phosphorylation of GSK-3β, which is involved in the phosphorylation of tau protein in the cerebral cortex of experimental animals.
In the Tg-TE group that was subjected to treadmill exercise for 12 weeks, abnormal mTOR phosphorylation of PI3K/AKT proteins was improved via increased phosphorylation and its activity was inhibited by increased GSK-3β phosphorylation compared with those in the Tg-CON group, which was used as the control group. In addition, the expression of Beclin-1 protein involved in autophagosome formation was increased in the Tg-TE group compared with that in the Tg-CON group, whereas that of p62 protein was reduced in the Tg-TE group compared with that in the Tg-CON group. Autophagy was activated owing to the increased expression of LC3-B that controls the completion of autophagosome formation. The hyperphosphorylation and aggregation (Ser199/202, Ser404, Thr231, PHF-1) of tau protein was found to be reduced in the Tg-TE group compared with that in the Tg-CON group. Furthermore, in the underwater maze test, the Tg-TE group showed a reduced escape time and distance compared with those of the Tg-CON group, suggesting that learning and cognitive ability were improved.
These findings suggest that aerobic exercise such as treadmill exercise might be an effective approach to ameliorate the pathological features (or neurofibrillary tangles) of Alzheimer's disease.
神经纤维缠结是阿尔茨海默病的病理特征之一，由tau蛋白的过度磷酸化和聚集产生。本研究旨在探讨跑步机运动对PI3K/AKT/mTOR信号传导、自噬以及与tau蛋白过度磷酸化和聚集相关的认知能力的影响。
将实验动物（NSE/htau23小鼠）分为非转基因对照组（Non-Tg-Control；CON；n = 7）、转基因对照组（Tg-CON；n = 7）和转基因运动组（Tg-Treadmill Exercise；TE；n = 7）。Tg-TE组进行12周的跑步机运动。跑步机运动完成后，通过进行水下迷宫测试来测定认知能力。进行蛋白质免疫印迹法以测定PI3K/AKT/mTOR蛋白和自噬相关蛋白（Beclin-1、p62、LC3-B）的磷酸化状态；tau蛋白的过度磷酸化和聚集（Ser199/202、Ser404、Thr231、PHF-1）；以及参与实验动物大脑皮质tau蛋白磷酸化的GSK-3β的磷酸化。
与作为对照组的Tg-CON组相比，进行了12周跑步机运动的Tg-TE组中，PI3K/AKT蛋白异常的mTOR磷酸化通过增加磷酸化得到改善，并且其活性因GSK-3β磷酸化增加而受到抑制。此外，与Tg-CON组相比，Tg-TE组中参与自噬体形成的Beclin-1蛋白表达增加，而与Tg-CON组相比，Tg-TE组中p62蛋白表达降低。由于控制自噬体形成完成的LC3-B表达增加，自噬被激活。与Tg-CON组相比，发现Tg-TE组中tau蛋白的过度磷酸化和聚集（Ser199/202、Ser404、Thr231、PHF-1）减少。此外，在水下迷宫测试中，与Tg-CON组相比，Tg-TE组的逃避时间和距离缩短，表明学习和认知能力得到改善。
这些发现表明，诸如跑步机运动之类的有氧运动可能是改善阿尔茨海默病病理特征（或神经纤维缠结）的有效方法。
