...Recently, microglia dysfunction leading to Aβ clearance impairment is proved an important mechanism for later Aβ deposition and AD pathogenesis. The present study aimed to confirm the effect of exercise on Aβ deposition and to investigate the role of microglia in exercise-induced Aβ reduction. In the present study, 3-month-old male APPswe/PS1dE9 (APP/PS1) mice and C57BL/6 wild-type mice were randomly divided into sedentary (SED) or exercise (EX) group, twelve mice in each group. Mice in exercise groups were subjected to ran on a treadmill for 3 months, 5 days/week. Afterwards, the spatial learning and memory, hippocampal fibrillar Aβ deposits and microglial functions were determined by Morris water maze task, methoxy-X04 staining as well as in vivo and in vitro assays, respectively. The results showed that 3 months of treadmill exercise largely prevented spatial learning and memory decline and alleviated hippocampal methoxy-X04-positive fibrillar Aβ deposits in APP/PS1 mice. Moreover, treadmill exercise partly restored microglial Aβ degradation and clearance in the hippocampus, which was impaired in APP/PS1 mice. However, the impaired microglial Aβ phagocytosis in APP/PS1 mice was not altered after 3 months of treadmill exercise intervention. These findings demonstrate that 3 months of treadmill exercise alleviates hippocampal Aβ deposition and restores spatial learning and memory in APP/PS1 mice, partly by promoting microglial Aβ degradation and clearance.