| Research PurposeThis study explores the role and mechanisms of aerobic exercise in delaying Alzheimer’s disease by regulating mitochondrial proteostasis through four aspects:mitochondrial unfolded protein response,mitochondrial autophagy,mitochondrial protein import,and mitochondrial protein deacetylation levels.This provides new ideas and theoretical basis for improving and delaying Alzheimer’s disease through aerobic exercise in the future.Research MethodsSixty male APP/PS1 mice were randomly divided into three groups: the normal group(NG,n=20),the activation group(AG,n=20),and the inhibition group(SG,n=20).The AG was administered with mitochondrial proteostasis activator nicotinamide riboside(NR)through gavage,while the SG was administered with mitochondrial proteostasis inhibitor chloroquine through injection.Once a day for a total of thirteen weeks of intervention.Meanwhile,each group of mice was further randomly divided into a sedentary control group and an aerobic exercise group,with ten mice in each group,namely,normal control group(CNG,n=10),normal exercise group(ENG,n=10),activation control group(CAG,n=10),activation exercise group(EAG,n=10),inhibition control group(CSG,n=10),and inhibition exercise group(ESG,n=10).In addition,twenty APP/PS1 mice and ten C57 wild-type mice were randomly selected,C57 wild-type mice as wild-type normal control group(CWG,n=10),and the APP/PS1 mice were randomly divided into a normal control group(CNG,n=10)and a normal exercise group(ENG,n=10).After one week of adaptive training,all mice in the exercise groups underwent twelve weeks of aerobic treadmill training,followed by Morris water maze and the Step-Down test in the fourteenth week.Tissue samples were then taken for quantitative real-time PCR and Western blot analysis to evaluate various indicators of every groups.Research Results(1)Through the Morris water maze experiment,the differences in the escape latency and the number of platform-site crossings of CNG,ENG,CAG,EAG,CSG,and ESG mice under the conditions of mitochondrial proteostasis activation and inhibition were compared and analyzed.It was found that compared with the CNG,the escape latency of the ENG and CAG were significantly reduced,and the number of platform crossings were significantly increased,while the results for CSG were contrary.Compared with the ENG,the escape latency of the EAG was significantly reduced,and the number of platform crossings was significantly increased,while the results for ESG were contrary.Compared with the CAG,the escape latency of the EAG group was significantly reduced,and the number of platform crossings was significantly increased,while the results for CSG were contrary.Compared with the EAG the escape latency of the ESG was significantly increased,and the number of platform crossings was significantly decreased.Compared with the CSG,the escape latency of the ESG was significantly decreased and the number of platform crossings was significantly increased.(2)Through the Step-Down test,the differences in step-down latency and the number of error times of CNG,ENG,CAG,EAG,CSG,and ESG mice under the conditions of mitochondrial proteostasis activation and inhibition were compared and analyzed.It was found that compared with the CNG,the step-down latency of the ENG and CAG were significantly increased,and the number of error times were significantly decreased,while the step-down latency of the CSG was decreased but did not reach significant difference,and the number of error times was significantly increased.Compared with the ENG,the step-down latency of the EAG was significantly increased,and the number of error times was significantly decreased,while the results for ESG were contrary.Compared with the CAG,the step-down latency of the EAG was significantly increased,and the number of error times was significantly decreased,while the results for CSG were contrary.Compared with the EAG,the step-down latency of the ESG was significantly decreased,and the number of error times was significantly increased.Compared with the ESG,the step-down latency of the CSG was decreased but did not reach significantly difference,and the number of error times was significantly increased.(3)Through the quantitative real-time PCR and Western blot analysis,the mRNA and protein levels of mitochondrial unfolded protein response in cerebral cortex and hippocampus of mice in CNG,ENG,CAG,EAG,CSG and ESG groups were detected.It was found that compared with the CNG,the mRNA and protein levels of the ENG and CAG were significantly increased,while the results for CSG were contrary.Compared with the ENG,the mRNA and protein levels of the EAG were significantly increased,while the results for ESG were contrary.Compared with the CAG,the mRNA and protein levels of the EAG were significantly increased,while the results for CSG were contrary.Compared with the EAG,the mRNA and protein levels of the ESG were significantly decreased.Compared with the CSG,the mRNA and protein levels of the ESG were significantly increased.(4)Through the quantitative real-time PCR and Western blot analysis,the mRNA and protein levels of mitochondrial autophagy in cerebral cortex and hippocampus of mice in CNG,ENG,CAG,EAG,CSG and ESG groups were detected.It was found that compared with the CNG,the mRNA and protein levels of the ENG and CAG were significantly increased,while the results for CSG were contrary.Compared with the ENG,the mRNA and protein levels of the EAG were significantly increased,while the results for ESG were contrary.Compared with the CAG,the mRNA and protein levels of the EAG were significantly increased,while the results for CSG were contrary.Compared with the EAG,the mRNA and protein levels of the ESG were significantly decreased.Compared with the CSG,the mRNA and protein levels of the ESG were significantly increased.(5)Through the quantitative real-time PCR and Western blot analysis,the mRNA and protein levels of mitochondrial protein import in cerebral cortex and hippocampus of mice in CNG,ENG,CAG,EAG,CSG and ESG groups were detected.It was found that compared with the CNG,the mRNA and protein levels of the ENG and CAG were significantly decreased,while the results for CSG were contrary.Compared with the ENG,the mRNA and protein levels of the EAG were significantly decreased,while the results for ESG were contrary.Compared with the CAG,the mRNA and protein levels of the EAG were significantly decreased,while the results for CSG were contrary.Compared with the EAG,the mRNA and protein levels of the ESG were significantly increased.Compared with the CSG,the mRNA and protein levels of the ESG were significantly decreased.(6)Through the Western blot analysis,the protein levels of the protein deacetylation level in cerebral cortex and hippocampus of mice in CWG,CNG,ENG groups were detected.It was found that compared with the CWG,the protein levels of the CNG were significantly decreased.Compared with the CNG,the protein levels of the ENG were significantly increased.Compared with the CWG,the protein levels of the ENG were significantly decreased.Research ConclusionAerobic exercise can improve cognitive function and delay Alzheimer’s disease symptoms in APP/PS1 mice by regulating mitochondrial proteostasis.The specific mechanisms are:(1)Aerobic exercise reduces the accumulation pressure of mitochondrial unfolded or misfolded proteins and maintain mitochondrial proteostasis by activating unfolded mitochondrial protein reaction.(2)Aerobic exercise removes damaged or abnormal mitochondria and maintain mitochondrial proteostasis by promoting mitochondrial autophagy.(3)Aerobic exercise reduces the burden of mitochondrial chaperones and proteases and maintain mitochondrial proteostasis by reducing mitochondrial protein import.(4)Aerobic exercise upregulating the main mitochondrial deacetylase and its regulatory proteins and maintain mitochondrial proteostasis by increasing mitochondrial protein deacetylation levels. |
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