The Effects Of Treadmill Exercise On PI3K/AKT/mTOR Signaling Pathway And Autophagy In Hippocampus Of APP/PS1 Transgenic Mice

Background:Alzheimer’s disease is a neurodegenerative disease, which is often diagnosed in older adults.With the rapid rise number of the aging population, there’s no doubt that this disease will cause heavy burden to the country.At present, the neural pathological features observed in the brain of AD include the accumulation of senile plaques and the entanglement of the nerve fibers.The main component of senile plaques is Aβ. Up to now,the pathogenesis of AD is still not clear, but the neurotoxicity induced by Aβ is regarded as the core mechanism of AD.Effective method has not been found to cure AD eompletely.Meanwhile,drug therapy can only alleviate the pathological development of AD.What’s more,more toxic and side effects may be caused.In recent years,the occurrence of aerobic exercise plays a significant role on the prevention and treatment of AD.Many animal studies have demonstrated that the major benefits of exercise can improve the brain structure and function of AD mice, and it also can improve the ability of learning and memory. However,the specific molecular mechanism about how exercise inhibit the deposition of Aβ in the hippocampus of AD mice is still needed to explore.Recent studies have found that the occurrence of AD is closely related to autophagy. In brain with AD,a large and abnormal number of autophagosome can be observed,indicating that there is a dysfunction of autophagy. Autophagy plays an important role in the removal of toxic/aggregation proteins and damaged organelles.Furthermore,in the process of AD pathology,the activity of PI3K/Akt/mTOR signaling pathway was closely related to the disorder of autophagy.This study do research relatively based on association between them.Using APP/PS1 transgenic mice as objects of the experiments, this study aim to explore the effects of treadmill training on spatial learning and memory ability、the changes of PI3K/Akt/mTOR signaling pathway in mice hippocampus and the launch of autophagy,which utilizing the treadmill training as a means of intervention.Methods:There are 12only 3months APP/PS1 transgenic C57BL/6 mice and the wild type C57BL/6 mice 12 only 3 months.Let them eat and drink freely in conventional cage and natural light. The APP/PS1 mice were randomly divided into 2 groups:quiet gm AD group (ADC, n= 6), gm AD campaign group (ADE, n=6), each group of 6; The wild type C57BL/ 6 mice were.randomly divided into quiet group (C, n= 6) and exercise groups (E, n=6), each group of 6. Group of the exercise mice need to adapt to the movement with the speed of 5m/min for 2 days.Then next 2 days,this group need to exercise with 8m/min and 12m/min, respectively.15 minutes are required each day.After the second week,mice were trained with the speed of 5-13m/min for 45min. After 12 weeks, for a six-day water maze experiment. Water maze after 24 h, index test. The PT-PCR method in mice.The hippocampus, PI3K, and Akt, mTOR and IGF-1 ULK1 gene transcription level; Adopt Western Bolt method to detect PI3K, and Akt and ULK1 protein expression levels.Results:(1) In place navigation test, the incubation period and the total distance of Group ADC are higher than Group C (P<0.05).Significantly,compared to Group ADC,the incubation period and the total distance of Group ADE are lower, (P<0.05).Meanwhile,there’s reduction of Group E,but there’s not a significant difference (P>0.05).After spatial probe test for one day, the times of Group ADC across platform was a significant reduction as to Group C (P<0.01).The times of across platform was significantly increased in Group E,compared to Group C, as well as time during platform quadrant (P<0.05).The times of Group ADE across platform was increase significantly,when we compare it to Group ADE.(2) Compared with Group C, In the mice hippocampus of Group E,the IGF 1 mRNA expression level are significantly higher (P< 0.05).The mRNA expression of IGF 1 level of ADC mice is not obvious.Compared with the ADC mice.mRNA expression levelof IGF 1 in ADE group occurs extremely significant increase (P< 0.01).(3) Compared with Group C, mRN A expression level of PI3K in hippocampus mice of Group E is significantly higher (P< 0.01).Compared with the Group ADC,, mRNA expression level of PI3K is significantly higher in the hippocampus of Group ADE mice (P< 0.05). Compared with Group ADC, the PI3K protein expression level is greater than the ADC group of mice,is significantly higher (P< 0.05).The hippocampus in mice of Group ADE,which is compared with ADC group,the PI3K protein expression level is significantly higher (P< 0.05). Compared with the ADC mice, the AKT protein expression levels of ADE mice is significantly higher (P< 0.05). Compared with group C, mTOR mRNA expression level in group E is significantly higher (P< 0.05).In ADC mice,the mTOR and mRNA expression levels are significantly raised (P< 0.01).Compared with the ADC mice, the less mTOR and mRNA expression level than ADE, has shown the significant difference. (P< 0.05).(4) Compared with Group ADC,the mRNA expression level of ULK1 in Group ADE is greater than the ADC group.. (P< 0.05). Compared with Group C, ULK1 protein expression level in Group E is greater than group C mice.Also,there is a significant difference between them (P<0.05). Compared with Group ADC the ULK1 protein expression levels in hippocampus of ADE mice is significantly higher (P< 0.05).Conclusion:(1)After 12 weeks of treadmill training,the APP/PS1 transgenic mice improve the spatial learning and memory ability.(2)In hippocampus of the APP/PS1 transgenic mice,IGF-1/PI3K/Akt signaling system was damaged.Benefit by 12 weeks of treadmill training,the signal transduction pathway was raised.(3)In hippocampus of the APP/PS1 transgenic mice, the gene transcription was activated abnormally and the autophagy levels was also dropped.The transcription levels was down-regulated by 12 weeks of treadmill training,as well as the up regulation transcription of ULK1.So that the autophagy was started.