Activation Of Proteasome Activity In Hippocampus Promotes Neurogenesis And Prevents A?_1-42-induced Cognitive Impairment In Mice

Objective:To observe the effect of short-term wheel running on proteasome activity and neurogenesis in hippocampus of middle-aged mice,and clarify whether long-term exercise can maintain proteasome activity to provent cognitive impairment induced by?-amyloid42(A?_1-42).Methods:1.Dissociated hippocampal tissues from Balb/c mice at the ages of newborn,1,3,12and 23 months.The proteasome activity and proteasome subunit gene expression level were measured by fluorescence spectrophotometry and qPCR.2.After 12 months-old mice running 4 weeks,the proteasome activity of tissues were measured including hippocampus,the subventricular zone,motor cortex,cerebellum and spinal cord.The effects of running on learning memory and spatial memory ability were tested by novel object recognition and Y maze spontaneous alternation.We stained DCX-early neuronal marker and Ki67-proliferating cell marker to detected neurogenesis.3.After 12 month-old mice running 6 months,Western blot was used to detect theaccumulation of ubiquited protein in hippocampus.And then,their hippocampus were injected with A?_1-42-42 to simulate the AD model.After 2 weeks,the proteasome activity and cognitive ability were measured.Results:1.The fluorescence spectrophotometry results showed that the proteasome activity decreased with aging.And as age increased,the gene expression level of proteasome subunit?1,?2,?5,and?3 decreased by degrees.2.After 12 month-old mice running for 4 weeks,as compared with the sedentary group,the proteasome activity of hippocampus,subventricular zone and motor cortex increased respectively?P<0.05?.However,the proteasome activity didn't change significantly in cerebellum and spinal cord.The novel preference index of runner group was higher than the sedentary?P<0.05?,and the correct rate of spontaneous alternation in runner group increased about 8.8%±3.6%?P<0.05?.In addition,the number of newborn neuron?DCX⁺?and proliferating cells?Ki67⁺?in the subgranular layer?SGZ?were increased significantly by exercise?P<0.05?,the length of outgrowth in DCX⁺cells increased 0.8 times?P<0.01?at the same time.3.After 12 month-old mice exercised for 6 months,the hippocampal ubiquitinated protein accumulation was 0.2 times lower than the sedentary group?P<0.05?.Thenbilateral hippocampal injection of A?_1-42-42 was used to observe whether long-term exercise could maintain the proteasome activity of hippocampal,and then provent the impairment of A?_1-42-42 on cognitive ability.The results showed that the proteasome activity of long-term exercise group had no difference with control group.The novel preference index in sedentary group was 44.8%±3.7%,which was significantly lower than that in control group,but there was no difference between the runner group and the solvent control group.And the correct rate of spontaneous alternation in runner group was higher than that of the sedentary group?P<0.05?,but in accordance with the solvent control group.Conclusion:Exercise enhance the proteasome activity of hippocampus to promote the cognitive ability and improve neurogenesis,it also can prevent the cognitive impairment induced by A?1-42.