The Effects Of Treadmill On The Reduction Of A? Through DNA Methylation In The APP/PS1 Mice

Background: Alzheimer's disease is a neurodegenerative disease associated with loss of short-term memory and the decreased learning and memory function.This disease is characterized by excessive production and accumulation of amyloid-beta in different regions of the brain,particularly in the hippocampus.Then,hippocampus is involved in the body's learning and memory functions,closely.A?1-42 which is nerotoxic is a major component of amyloid plaques in AD brain.Neurofibrillary tangles and senile plaques are recognized has been recognized as the core mechanism of AD.In recent years,many studies have suggested that exercise can have many beneficial effects on brain health,which includes prevention of AD-related cognitive decline.At present,epigenetics as a new hotspot,especially DNA methylation,has been reported in many aspects related to the pathogenesis of AD.Whether exercise can reduce A? through the change of DNA methylation is rarely studied at home and abroad.This study mainly used treadmill exercise as an intervention and APP/PS1 transgenic mice as the research objects to explore the effects of treadmill exercise changes on the reduction of A? through DNA methylation.Methods: 24 APP/PS1 mice and 24 wild-type mice as controls were randomly divided into 4 groups with 12 mice in each group: transgenic AD silent group(ADC,n=12)and transgenic AD quiet group(ADE,n=12),quiet group(WTC,n=12)and exercise group(WTE,n=12).In the adaptive phase,mice of the two exercise groups exercised for 5 days at a speed of 5m/min and exercised at a speed of 8m/min for 2 days.After that,they exercised at a speed of 12m/min for 2 days,exercised for 15 min every day,and closed on Saturday and Sunday.After the second week,exercise at a speed of 5-12m/min for 45 minutes.The specific method is to exercise for 5 minutes at the speed of 5m/min and 8m/min respectively,and then exercise for 30 minutes at 12m/min.After 12 weeks,behavioral tests were performed for a period of 6 days.The water maze experiment was conducted after the end of the experiment,and the corresponding indicators were tested.ELISA was used to detect the concentration of SAM and SAH in hippocampal tissue homogenate,and the ratio of SAM/SAH was calculated.The transcription levels of BACE1,DNMT1,DNMT3 a and DNMT3 b genes in hippocampus of mice were detected by RT-PCR method;The expression levels of DNMT1,DNMT3 a,DNMT3b and BACE-1 proteins were detected by was detected by Western Bolt method.Finally,immunohistochemistry was used to detect the deposition of senile plaques in the brain of mice.Results:(1)The hippocampal SAM level in ADC group mice was significantly lower than that in WTC group(p<0.01).Compared with ADC group,SAM level in hippocampus of ADE group mice was significantly higher(p<0.05);and when we compared the WTC group and the ADC group,we found that SAH levels of the ADC group in the hippocampus of the mouse group were significantly higher(p<0.01).Then,compared with the ADC group,the SAH level of the ADE group in the hippocampus was significantly lower(p<0.05);compared with the WTC group,the level of SAM/SAH of the ADC group mice in hippocampus was significantly lower(p<0.01).Compared with ADC group,SAM/SAH levels of ADE group in hippocampus were significantly higher(p<0.01).(2)Compared with WTC group,the m RNA level of DNMT1 in hippocampus of WTE was significantly higher(p<0.01),and m RNA level of DNMT1 in hippocampus of ADC group mice was significantly lower(p<0.05);compared with ADC group,the m RNA level of DNMT1 of ADE group in hippocampus of mice was significantly higher(p<0.01).Compared with WTC group,the protein level of DNMT1 in hippocampus of WTE group mice was significantly higher(p<0.05),and the protein level of DNMT1 in hippocampus of ADC group mice was significantly lower(p<0.05)Compared with the ADC group,the protein level of DNMT1 in the hippocampus of ADE was significantly higher(p<0.01).(3)Compared with WTC group,the mRNA level of DNMT3 a in hippocampus of WTE group mice was significantly higher(p<0.05),and m RNA level of DNMT3 a in hippocampus of ADC group was significantly lower(p<0.01).Compared with ADC group,which in the ADE group,the m RNA level of DNMT3 a in the hippocampus was significantly higher(p<0.01).Compared with the WTC group,the protein level of DNMT3 a in the hippocampus of the ADC group was significantly lower(p<0.05).Compared with the ADC group,the ADE group was the mouse hippocampus,the protein level of DNMT3 a was significantly higher(p<0.01).(4)Compared with the WTC group,the mRNA level of DNMT3 b of the ADC group was significantly lower(p<0.01)in the hippocampus.Compared with the ADC group,the DNMT3 b m RNA level of the ADE group was significantly higher(p<0.01)in the hippocampus;Compared with WTC group,the protein level of DNMT3 b of ADC group mice was significantly decreased(p<0.05)in hippocampus.Compared with ADC group,the protein level of DNMT3 b of ADE group mice was significantly higher(p<0.05)in hippocampus.(5)Compared with the WTC group,the ADC group m RNA level of BACE-1 was significantly higher in the hippocampus(p<0.01).Compared with the ADC group,the ADE group m RNA level of BACE-1 was significantly lower in the hippocampus(p<0.05).Compared with WTC group,the ADC group protein level of BACE-1 was significantly increased in mouse hippocampus(p<0.01).Compared with ADC group,the protein level of BACE-1 in hippocampus of ADE group mice was significantly decreased(p<0.05).(6)The main effects of gene and exercise on the level of SPs were extremely significant in mouse hippocampus(p<0.0001,p=0.0004),but the interaction between the two had no significant effect on the level of SPs in mouse hippocampus(p=0.1213).Further analysis showed that compared with the WTC group,the hippocampal SPs levels were significantly higher in the ADC group(p<0.01),and the hippocampal SPs levels in the ADE group were significantly lower than those in the ADC group(p<0.01).Conclusion:(1)Compared with control group,the hippocampus of 6-month-old APP/PS1 mice may have a decreased level of DNA methylation,which is characterized by a decrease in SAM content,an increase in SAH content.Also,a decrease of SAM/SAH,DNMT1,DNMT3 a,and DNMT3 b had been observed in our study.(2)The DNA methylation level was up-regulated by 12-week treadmill exercise in the hippocampus of 6-month-old APP/PS1 mice.The specific performance is to increase the content of SAM,SAM/SAH,decrease the content of SAH,and increase the key indicators of DNA methylation such as DNMT1,DNMT3 a and DNMT3 b.(3)Treadmill exercise about 12 weeks reduced BACE-1 transcription and protein levels in hippocampus of APP/PS1 transgenic mice and reduced A? deposition.