Study Of Treadmill Exercise Decreased Expression Of A? In Hippocampal Of APP/PS1 Mice By Regulating PI3K/Akt/HSP70 Signaling Pathways

Research Objective:Alzheimer's Disease is a neurodegenerative disease common in middle and old age.It's a important risk factor that ?-amyloid protein gathered in Alzheimer Disease.Research Find that the AD brain A? degradation and transport function is impaired,which prompting A? gathered to form A? oligomers,which exert A? neurotoxicity through the inhibition of PI3K/Akt pathway.HSP70 can regulate A? clear effect.Studies have shown that exercise can reduce deposition of A? and improve the learning and memory ability of AD mice,which may be related to that exercise activate the PI3K/Akt signaling pathway.We adopt 3-month-old male APP/PS1 transgenic mice and wild-type mice to confirm effect of 12-week treadmill exercise on spatial learning and memory ability and expression level of A? in hippocampus of APP/PS1 mice.Preliminarily explore the correlation between PI3K/Akt pathway and hsp70-mediated clearance of A?,providing theoretical support for exercise prevention and alleviation of AD.Research Methods:Eighteen 3-month-old male APP/PS1 transgenic mice and eighteen 3-month-old male wild-type C57BL/6 mice were used.APP/PS1 mice and wild-type mice were randomly divided into the control group and the exercise group.In other words,APP/PS1 mice were randomly divided into transgenic control group(ADC,n=12)and transgenic exercise group(ADE,n=12),wide type mice were randomly divided into wide type control group(WTC,n=12)and wide type exercise group(WTE,n=12).ADE and WTE groups have running 12 weeks at the age of 3-months-old.After 12 weeks of treadmill exercise,Morris water maze experiment was conducted to test the spatial learning and memory ability of mice.After the behavioral experiment,the animal was anesthetized and sacrificed,and the hippocampus was taken.Using immunofluorescence test A? deposition in hippocampus of mice,ELISA test A? protein expression levels in the hippocampus,Real-time PCR experiment test HSF1,HSP70,LRP1,RAGE and IDE mRNA level in mice hippocampal,using western blot experiments test PI3 K p110?,PI3 K p85?,Akt,p-Akt,HSP70,HSP40,BAG-1,LRP1,RAGE,IDE protein expression level in mice hippocampal.Research Results:(1)Exercise can alleviate recession spatial learning and memory ability in APP/PS1 mice: Place Navigation Test results revealed that compared with the WTC group,ADC group latency significantly increased(P<0.01),the platform quadrant time percentage significantly reduced(P<0.01),compared with the ADC group,latency of ADE group significantly decreased(P<0.05),the platform quadrant time percentage of ADE group significantly increased(P<0.01).In space exploration experiments,compared with the WTC group,ADC group platform quadrant distance percentage significantly increased(P<0.05),the platform quadrant time percentage significantly increased(P<0.01),the crossing times significantly increased(P<0.01),compared with the ADC group,ADE platform quadrant percentage of mice significantly increased(P<0.01),the platform quadrant time percentage significantly increased(P<0.01),the platform through the number significantly increased(P<0.05).(2)Exercise can reduce the expression level of A? in the hippocampus of APP/PS1 mice: the result of Immunofluorescence revealed that compared with WTC group,area fraction of A? plaques in the hippocampus of ADC group significantly increased(P<0.01).Compared with ADC group,area fraction of A? plaques in the hippocampus of ADE group significantly reduced(P<0.01).the results of ELISA revealed: compared with WTC group,the expression of A?40 and A?42 in the hippocampus of ADC group was significantly increased(P<0.01);compared with ADC group,ADE group was significantly decreased(P<0.01).(3)Exercise can activate the PI3K/Akt signaling pathway in the hippocampus of APP/PS1 mice: the result of Western Blot experiment revealed that compared with WTC group,the protein expressions of PI3 K p38?,PI3 K p110? and p-Akt/Akt in the hippocampus of ADC group were significantly reduced(P<0.01).Compared with ADC group,the protein expression of PI3 K p38? in the hippocampus of ADE group was significantly increased(P<0.01),and the protein expression of PI3 K p110? and p-Akt/Akt were significantly increased(P<0.05).(4)Exercise can activate HSPs then fold in the APP/PS1 mice hippocampal function: the result of Real-time PCR experiment revealed that compared with the WTC group,HSF1 mRNA expression in the hippocampus in ADC mice significantly reduced(P<0.05),the mRNA expression of HSP70 has no significant change(P>0.05),compared with the ADC group,HSF1,mRNA expression of HSP70 in hippocampal of ADE group significantly increased(P<0.05).the result of Western Blot experiment revealed that compared with the WTC group,the expression of HSP70 and BAG-1 proteins in the hippocampus of the ADC group significantly decreased(P<0.01),while the expression of HSP40 proteins had no significant change(P>0.05).Compared with the ADC group,the expression of HSP70,HSP40 and BAG-1 proteins in the ADE group significantly increased(P<0.01).(5)Exercise can promote the clearance of hippocampus A? in APP/PS1 mice: the result of Real-time PCR experiment revealed: compared with the WTC group,the mRNA expression of LRP1,IDE in hippocampus of mice ADC group were significantly reduced(P<0.01),the mRNA expression of RAGE significantly increased(P<0.01);compared with the ADC group,the mRNA expression of LRP1 in the hippocampus of ADE group mice significantly increased(P<0.05),the mRNA expression of RAGE in the hippocampus of ADE group mice significantly increased(P<0.05),the IDE mRNA expression in the hippocampus of ADE group mice was significantly increased(P<0.01).the result of Western Blot experiment revealed: compared with the WTC group,protein expression LRP1 in the hippocampus of ADC group were significantly reduced(P<0.01),the protein expression of RAGE were significantly increased(P<0.01),the protein expression of IDE performance significantly reduced(P<0.05),compared with the ADC group,ADE group LRP1 protein expression in hippocampus of mice was very significantly increased(P<0.01),less RAGE protein expression was very significant(P<0.01),IDE protein expression was significantly increased(P<0.05).Research Conclusion:Our research indicates that exercise can improve AD by activating the PI3K/Akt signaling pathway.Exercise activates the PI3K/Akt signaling pathway and increases the expression of HSP70 and its coproteins,and inhibits A? aggregation.On the other hand,exercise activates the PI3K/Akt signaling pathway to up-regulate HSP70,induce the expression of IDE and LRP1,promote the clearance of A?,and improve the spatial learning and memory ability of mice.