| Objective: Aerobic exercise intervention was carried out on 3-month-old APP/PS1 double transgenic(Alzheimer's disease,AD)mice with Alzheimer's disease for 20 weeks to observe the effects of aerobic exercise on spatial learning and memory ability and hippocampal neurogenesis in AD mice,and to explore whether aerobic exercise affects(Adult hippocampal neurogenesis,AHN),in adult hippocampal neurogenesis of AD mice through Notch signal pathway.The purpose of this study is to provide a theoretical basis for aerobic exercise to delay the occurrence of AD and improve cognitive impairment.Methods: Twelve 3-month-old C57BL/6 male mice were randomly used as wild control group(WT),and 24 3-month-old male APP/PS1 double transgenic AD mice were randomly divided into AD control group(ADC group,n=12)and AD exercise group(ADE group,n=12).After feeding adaptively for 1 week,mice in ADE group underwent aerobic treadmill training for 20 weeks,once a day,5 days a week.The treadmill speed was 8m/min for the first two days,and the duration was 30min/d.Then the treadmill speed increased from 12m/min to 15m/min,the duration increased from10min/d to 20min/d,and the exercise load of 30min/d lasted for 20 weeks;WT and ADC groups were fed naturally for 20 weeks.After all interventions,Morris water maze and eight-arm maze were used to observe the changes of spatial learning and memory ability of mice After Morris water maze test and eight-arm maze test,samples were taken.The hippocampal tissues of all mice were isolated,and the expression levels of A-1-42,DCX,Notch1 and Hes1 in the hippocampus of mice were detected by Real-time PCR,Western Blotting(WB)and immunofluorescence(IF).Results: 1.Morris water maze results:(1)Position navigation experiment results:During the 6-day positioning navigation training,the average escape time of mice in each group was gradually shortened with the increase of training times.The average escape latency time of mice in each group on the same day was compared and analyzed,and it was found that the WT group and ADE group were shorter than ADC group.There was no significant difference in escape incubation period on the first day among the groups(P > 0.05);From the first day to the last training period,the escape incubation period of ADC group was significantly longer than that of WT group(P <0.01);From the second day,the escape incubation period of ADE group was significantly shorter than that of ADC group(P < 0.01),but the escape incubation period of ADE group was not significantly different from that of WT group(P > 0.05).(2)The results of space exploration experiment: the time of staying in the target quadrant and the number of times of crossing the original platform in the ADC group were significantly less than those in the WT group(P < 0.01),while the time of staying in the target quadrant and the number of times of crossing the original platform in the ADE group were significantly lower than those in the WT group after aerobic exercise intervention(P < 0.05);Compared with the ADC group,the stay time in the target quadrant and the number of times of crossing the original platform in the ADE group increased(P < 0.01).2.Eight-arm maze results:(1)On the number of working memory errors,the number of errors in ADC group mice was the highest,and the number of errors in ADC group mice was significantly higher than that in WT group mice(P < 0.01),while the number of errors in ADE group mice was slightly lower than that in WT group mice(P< 0.05);In addition,the number of errors in ADC group was significantly higher than that in ADE group(P < 0.01);(2)On the number of reference memory errors: ADC group mice have the most errors,while ADE group mice have slightly better performance than WT group mice(P < 0.05);The number of errors in ADC group was significantly higher than that in ADE and WT groups(P < 0.01).3.Molecular biology detection results:(1)Real-time PCR results: The expression of A1-42 m RNA in hippocampus of mice in ADC and ADE groups was significantly higher than that in WT group(P < 0.01);The expression of A1-42 m RNA in hippocampus of ADE group was significantly lower than that of ADC group(P < 0.01);The expression of DCX m RNA in hippocampus of WT and ADE mice was higher than that of ADC group,and there were significant differences(P < 0.01);The expression of Notch1 m RNA in hippocampus of ADE mice was significantly lower than that of ADC group(P < 0.01).The expression of Hes1 m RNA in hippocampus of ADC group was significantly higher than that of ADE group(P < 0.01).(2)Western blotting results:The expression of A1-42 protein in the hippocampus of ADC group mice was significantly higher than that of WT group,ADE group(P < 0.01),ADE mice A1-42 protein expression in the hippocampus was significantly higher than that of WT group(P < 0.05);The expression of DCX protein in the hippocampus of ADC group was significantly lower than that of WT group,ADE group(P < 0.01),and the expression of DCX protein in the hippocampus of ADE group was slightly higher than that of WT group(P < 0.05);The expression of Notch1 protein in hippocampus of ADC group was significantly higher than that of ADE group(P < 0.01);The expression of Hes1 protein in hippocampus of ADE group was significantly lower than that of ADC group(P <0.01).(3)The results of immunofluorescence reaction: The IOD value of hippocampus A1-42 in ADC and ADE groups was significantly higher than that in WT group(P <0.01)(P < 0.05),and the IOD value of ADE group was significantly lower than that of ADC(P < 0.05);The IOD value of DCX in hippocampus of WT and ADE groups was significantly higher than that of ADC group(P < 0.01),and the IOD value of ADE group was slightly lower than that of WT group(P < 0.05);Notch1 IOD value in hippocampus of ADE group was significantly lower than that of ADC group(P < 0.01);The hippocampal Hes1 IOD value of ADE group was significantly lower than that of ADC group(P < 0.01).Conclusion: 1.After aerobic exercise intervention,the expression of DCX in the DG area of the hippocampus of APP/PS1 mice is up-regulated,and the expression of A1-42 is down-regulated,suggesting that regular aerobic exercise may enhance the neurogenesis of the adult hippocampus of mice,reduce the deposition of senile plaques,and have a certain effect on AD mice.Improve cognitive impairment.2.After aerobic exercise intervention,the expression of DCX in the DG area of the hippocampus of APP/PS1 mice is up-regulated,and the expression of A1-42 is down-regulated,suggesting that regular aerobic exercise may enhance the neurogenesis of the adult hippocampus of mice,reduce the deposition of senile plaques,and have a certain effect on AD mice.Improve cognitive impairment.3.Aerobic exercise intervention can down-regulate the expression of Notch1 and Hes1 in the hippocampus of APP/PS1 mice,suggesting that the improvement of learning and memory ability of AD mice by aerobic exercise may be related to the regulation of Notch signaling pathway. |
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