Effect Of Exercise On Improving Cognitive Impairment By Regulating Iron Homeostasis In Hippocampus Of APP/PS1 Mice

Objective:In this study,a 20-week aerobic exercise intervention was performed in 3-month-old male APP/PS1 double-transgenic mice to explore the effects of aerobic exercise on the expression of iron homeostasis-related proteins and learning and memory ability in the hippocampus of AD mice.Methods:The subjects were randomly divided into AD model exercise intervention group（AE group,n=12）and AD model control group（AD group,n=12）and 24 male APP/PS1 double transgenic mice selected by 3 months.Twelve male wild-type C57BL/6J mice were treated as WT wild control group（WT group,n=12）.One week after adaptive feeding,the AE group was trained on the treadmill with an exercise intensity of 15m/min,each exercise time was 30min,and the exercise continued for 20 weeks.After the motor intervention,MWM experiment was performed on each group of mice to test the ability to locate navigation and space exploration.After the test,mouse brain tissue was taken and the number of hippocampal iron ions was observed by Prussian blue staining.WB was is used to detect the protein content of TfR1,DMT1,Fpn1,and Cp.IF technology was used to detect the expression of Aβ_1-42in the hippocampus of each group of mice.Results:（1）Observation of signs and weight:The mice in the WT group had good food intake and mental state,normal range of activity in the cage,and normal weight gain.The mice in the AD group ate less,had fights,and gained weight slowly;The mice in the AE group had less food intake,few fights,no injuries,and the weight of the AE group increased compared with the AD group after aerobic exercise intervention.（2）The results of the Morris water maze showed that during the positioning navigation experiment,the AD group had a slow downward trend,while the AE group always showed a downward trend.From the fourth day,the average escape latency time of the AE group was significantly lower than that of the AD group（P<0.05）.There was no significant difference in the average swimming speed among the mice in each group（P>0.05）,indicating that the swimming speed did not affect the difference in escape latency among the mice in each group.The results of the space exploration experiment showed that the number of crossing platforms in AD group was lower than that in WT group（P<0.05）,and the number of crossing platforms in AE group was higher than that in AD group（P<0.05）.（3）The quantitative analysis of Prussian blue staining showed that compared with the WT group,the blue spots in the AD group were significantly increased（P<0.01）,and the AD group showed a significant increase in iron ions.Compared with the AD group,the blue spots in the AE group were significantly reduced（P<0.05）.（4）The results of immunofluorescence quantitative analysis showed that the expression of Aβ_1-42protein in each group of mice was significantly lower in the WT group than in the AD group and AE group（P<0.01）,and the AE group was significantly lower than the AD group（P<0.01）.（5）The results of Western Blot experiment showed that compared with AD group,the expression of TfR1 protein in WT group and AE group was significantly decreased（P<0.01）;compared with AD group,the expression of DMT1protein in WT group and AE group was significantly decreased.（P<0.01）;Compared with AD group,the expression of Fpn1 protein in WT group and AE group was significantly increased（P<0.01）;compared with AD group,CP protein expression in WT group and AE group was significantly increased（P<0.01）.Conclusion:（1）The 20-week aerobic exercise intervention could improve spatial learning and memory in APP/PS1 mice.（2）The 20-week aerobic exercise intervention reduced iron ion accumulation in the DG region of the hippocampus of APP/PS1 mice.（3）The 20-week aerobic exercise intervention reduced the expression level of hippocampal Aβ1-42 in APP/PS1 mice,reduced the expression of TfR1 and DMT1 in the hippocampus of APP/PS1 mice,and increased the expression of hippocampal Fpn1 and Cp in APP/PS1 mice,suggesting that aerobic exercise may improve cognitive impairment in AD mice by protecting neurons and regulating iron homeostasis.