Abstract: Objective　To observe the mechanism of cognitive dysfunction caused by Aβ-amyloid 1-42 (Aβ1-42) in middle-aged and elderly mice by long-term exercise.　Methods 　12-month-old BABL/c mice were randomly divided into the following four groups:①a vehicle control sedentary group (VS),②a vehicle control long-term voluntary running wheel exercise group (VR), ③an Aβ1-42 sedentary group (AS),④an Aβ1-42 long-term voluntary running wheel exercise group (AR). Voluntary running wheel exercise or sedentary for 6 months was performed according to the grouping conditions. The bilateral hippocampus was injected with Aβ1-42 or equivalent solvent for 6 months.  Tests were performed two weeks after injection.    Results　Western blotting results showed that the accumulation of ubiquitinated protein in the hippocampus of 12-month-old BABL/c mice after long-term voluntary exercise was significantly lower than that in the sedentary group by about 0.2 times (P<0.05). The novel object recognition experiment showed that the preference index in the AR group was 0.42 times higher than that in the AS group（P<0.05). The spontaneous alternation experiment of Y maze showed that the correct rate of arm entry in AR group increased than that in AS group by about 0.21 times (P<0.05). The proteasome activity of AR hippocampus was significantly higher than that of AS group by about 0.18 times (P<0.05). Western blotting results showed the accumulation of ubiquitinated protein in the hippocampus in the AR group was significantly lower than that of AS group by about 0.21 times (P<0.05).  Immunohistochemical results showed that Aβ1-42 deposition in AR group was lesser（P<0.01).　Conclusions Middle-aged and elderly mice can maintain hippocampal proteasome activity and improve the cognitive dysfunction caused by Aβ1-42 through long-term voluntary running wheel exercise. 

Key words: Middle-aged and elderly mice, 　Long-term exercise, 　Aβ1-42, 　Proteasome activity, Cognitive dysfunction