LONG-TERM AEROBIC EXERCISE REDUCES TAU PHOSPHORYLATION BY ACTIVATING THE PI3K/AKT PATHWAY IN THE HIPPOCAMPUS OF APP/PS1 MICE

Many studies suggest that regular physical activity can reduce the opportunity of Alzheimer’s disease (AD) and slow its onset and progression. However, the exact mechanism is still unclear. Clinically, amyloid plaques and neurofibrillary tangles are the two characterizations of AD, which are associated with amyloid-[Formula: see text] and tau hyperphosphorylation, respectively. The PI3K/Akt signaling pathway regulates tau phosphorylation and has a pivotal role in the development of pathology in AD. Therefore, we try to investigate the effects of aerobic exercise on tau phosphorylation and examine whether these effects were mediated by the PI3K/Akt pathway in the hippocampus of APP/PS1 and C57BL/6J mice. 40 male APP/PS1 mice and 40 male C57BL/6J mice were randomly divided into four groups respectively: sedentary group, exercise group, sedentary with GNE-317 treatment group and exercise with GNE-317 treatment group. The mice in the exercise group and exercise with GNE-317 treatment group were given exercise training on a treadmill for 8 weeks. After 8 weeks of treadmill exercise, the morris water maze, immunohistochemistry and western blot analysis were performed. We found out that 8 weeks of aerobic exercise enhanced PI3K expression and increased p-Akt[Formula: see text], p-Akt[Formula: see text] and p-GSK3[Formula: see text]. Furthermore, 8 weeks of aerobic exercise reduced tau phosphorylation at multiple sites including Ser202, Thr231 and Ser396. In the morris water maze, the exercise group showed a reduced escape time and distance compared with those of the sedentary group, suggesting that aerobic exercise improved the cognitive ability in mouse. While the above-mentioned results were attenuated in the PI3K/Akt inhibitor GNE-317 treatment groups. Our study demonstrated that 8 weeks of aerobic exercise could reduce tau phosphorylation and improve cognitive functions by activating the PI3K/Akt pathway in the hippocampus of APP/PS1 and C57BL/6J mice.