Effect Of Aerobic Exercise On Mitochondrial Permeability Transition Pore Function In Central Neuron Of APP/PS1 Transgenic Mice

Objective: To investigate the effect of 12 weeks aerobic exercises on mitochondrial permeability transition pore function in the central neurons of 9-month-old APP/PS1 transgenic mice.Methods:(1)APP/PS1 transgenic mice(6-month-old)and C57BL/6J mice(6-month-old)were randomly divided into 12 weeks exercise(CE,AE)and sedentary(AS,CS)respectively.(2)The behavioral changes was detected by eight arm experiment to observe the frequency of working memory errors and frequency of reference memory errors.(3)The brains were subjected to immunofluorescence and immunohistochemistry and Dotblot to analyze the level of amyloid-?(A?)and soluble amyloid-? peptide oligomers(o A?).(4)Mitochondrial permeability transition pore open in the brain tissue was detected by immunofluorescence.(5)ELISA was used to detect the activity of COXIV,ABAD in the cortex and hippocampus.(6)The protein levels of COXIV?ABAD?Cyp-D?ANT1?ANT2?VDAC-1 were measured using Western Blotting.Results:(1)Behaviorally: there was significant changes in 9-month-old AS compared with the control cohorts(CS)in both frequence of reference memory errors and frequence of working memory errors(P<0.05).The AE mice performed significantly better than those of AS in both frequence of reference memory errors and frequence of working memory errors(P<0.05).Also the CE mice performed significantly better than those of CS in both frequence of reference memory errors and frequence of working memory errors(P<0.05).(2)CE animals showed decreaed o A? levels compared with CS mice.A? was aggregated at cortex and hippocampus in 9-month-old APP/PS1 transgenic mice(AS)and accompanied with a markedly increase of o A?(P<0.05).There was a decline detected in A? plaque burden and o A? content in AE than those of AS(P<0.05).(3)There was a significant increase in 9-month-old AS compared with the control cohorts(CS)in the mitochondrial permeability transition pore opening(P<0.05),and which was significantly decreased after aerobic exercise training(P<0.05).(4)9 month-old APP/PS1 mice displayed a prominent increase in Cyp-D?ANT1?VDAC-1 protein levels of the cortex and hippocampus compared with the CS controls(P<0.05),but a decrease in ANT2 protein(P<0.05).Aerobic exercise decreased the expression of Cyp-D?ANT1?VDAC-1 in APP/PS1 mice and increased ANT2(P<0.05).(5)The expression of COXIV in the temporal lobe and hippocampus of 9 month-old APP/PS1 mice were decreased and ABAD expression was increased in hippocampus(P<0.05).12 weeks aerobic exercise resulted in a dramatical increase in COXIV and a decrease the expression of ABAD(P<0.05).(6)The activity of COXIV and ABAD in the cortex and hippocampus of 9 month-old APP/PS1 mice were decreased compared with those of the CS group(P<0.05).Aerobic exercise caused a significant increase in activity of COXIV and ABAD(temporal lobe and hippocampus)in APP/PS1 mice.(7)As to the control cohorts,aerobic exercise induced a decrease in Cyp-D level and an increase in ANT2,COXIV protein and the COXIV activity in the brain(P<0.05),thus resulted in a decrease in MPTP opening.Conclusion: Our findings suggest that the effects on transgenic mice,including inhibiting A? production and deposition,reducing the interaction between A? and Cyp D?ANT1?ANT2?VDAC-1,then regulating the opening level of MPTP,and strengthening the mitochondrial energy metabolism by up-regulating the activity of ABAD and COXIV,may be an important molecular mechanism of exercise-induced spatial learning and memory ability.