| Alzheimer's disease(AD)is one of the major healthy challenge among the aging population worldwide.It is considered a frequent cause of dementia,and increasingly contributes to the global mortality.With the emergence of population aging problem,the treatment of AD attracts more and more attention and urgently needs to be improved.Neuroinflammation is a common hallmark in the pathogenesis of AD.The continuous neuroinflammation induced by the aberrant activation of microglia,leading to the damage and apoptosis of neurons and glial cells.Thus,emerging studies have focused on the methods that could inhibit neuroinflammation to improve and exploit novel therapeutic approaches for AD.Current evidence provides a compelling argument for the participation in moderate physical exercise,consisting of both aerobic and resistance training,as a strategy for improving cognitive function and preventing cognitive decline,perhaps preventing the development of dementia and other neurodegenerative diseases,such as Parkinson's disease(PD)and AD.Physical exercise has been reported to improve the age-or disease-associated atrophy in brain,indicating its protective potential against cognitive decline.Further investigations in the past few years have confirmed that physical exercise has significant protective effects on the cognitive function in the elderly.However,the understanding about the molecular mechanisms responsive for the protective role of physical exercise remains limited,Neurodegenerative diseases and a wide variety of inflammatory conditions are linked together and several anti-inflammatory compounds considered as having therapeutic potential for the disease.AD is a neurodegenerative disorder associated with neuroinflammation,as indicated by activated microglia and elevated levels of pro-inflammatory cytokines.Some inflammatory cytokines,such as interleukin(IL)-1?,IL-6 and tumor necrosis factor(TNF)-a,have been found to be suppressed in AD patients with physical exercise,which indicated that physical exercise could attenuate the neuroinflammation of AD.MicroRNAs(miRNAs)are a group of small noncoding RNAs with important regulatory function in various cellular and molecular processes.MiRNA functions in the post-transcriptional regulator of gene expression by targeting the 3'UTR of mRNAs.Aberrant expression of miRNAs have been identified in the development of AD,and these functional miRNAs are determined as potential targets for the treatment of this disease.Some of these miRNAs are found to be involve in the progression of AD through the regulation of neuroinflammation.MicroRNA-129-5p(miR-129-5p)has been reported to inhibit neuroinflammation in ischemia-reperfusion injury in spinal cord.However,few research have focused on the role of miR-129-5p in AD progression.Physical exercise has been reported to improve the cognitive dysfunction by regulating miR-132 in AD.A study by Valenti et al.has gave evidence for that physical exercise increases the expression of miR-129-5p in progenitor cells promoting osteogenesis.Thus,we deduced that miR-129-5p might also be regulated by the physical exercise in AD.To further uncover the molecular mechanisms underlying the protective influence of physical exercise in AD,this study aimed to investigate the role of miR-129-5p in the effects of physical exercise on the cognitive function and neuroinflammation in both the AD mice and patients.Part I The role of physical exercise in Alzheimer's DiseaseObjectiveWith the increasing proportion of the elderly in modern society,the cognitive loss of the elderly has become the primary problem faced by public health institutions.Exercise is considered a potential lifestyle intervention that may play a role in the development of AD.This study aimed to investigate the effects of physical exercise on cognitive impairment and neuroinflammatory levels in patients with ADMethodsA total of 80 AD patients were recruited in this study,and randomly grouped into exercise group(n=40)and matched group(n=40).The patients in exercise group received cycling training with 70%maximum heart rate for 3 months.And the patients in matched group were underwent the health education for 3 months and asked to live by the past without aerobic exercise.Serum samples were collected from each participant.The function features of the patients were evaluated,including minimum mental state examination score(MMSE),neuropsychiatric inventory questionnaire score(NPI-Q),and Alzheimer's disease assessment scale-cognition score(ADAS-cog).8 months old APP/PS1(APPswe/PSEN1dE9)double Tg mice were purchased as the AD animal model,which were divided randomly into control group and voluntary exercise group(VE),The mice in the VE group were individually housed in cages with running wheels,to undergo voluntary exercise for 4 weeks,while the mice in control group were housed individually in cages with immobilized running wheels.The cognitive function of the mice was estimated using the Morris water maze test(MWM).After experiments,the mices were euthanatized and their hippocampus tissues were collected.The key pro-inflammatory cytokines,including IL-1?,IL-6 and TNF-?,in the hippocampus supernatant and patients' serum specimens were measured using the enzyme-linked immunosorbent assay(ELISA)ResultsThe psychological status of AD patients before and after exercise was evaluated.It was noted that compared with the matched group,the MSSE score increased significantly in AD patients after physical exercise,while the ADAS-Cog and NPI-Q increased significantly.The MWM results indicated that compared with the control group the latency to find the hidden platform and distances traveled during the test for mice were decreased in the VE group,while the time spent in the target quadrant and crossings through the original platform location increased significantly.The ELISA results showed that the relative levels of IL-1?,IL-6,and TNF-? were all reduced for mice in the VE group compared with that in the control group.ConclusionPhysical exercise improved the cognitive impairment of AD and inhibited the release of inflammatory cytokinesPart ? The effect of physical exercise on the expression levels of miR-129-5pObjectiveIn recent years,increasing researches prove that changes in microRNA(miRNA)expression patterns may be involved in the progression of AD and play a role in the risk of the disease.Physical exercise can improve cognitive dysfunction by regulating miRNA levels in AD.It has been reported that miR-129-5p is involved in the neuroinflammatory response in spinal cord ischemia-reperfusion injury.Therefore,the study aimed to explore whether miR-129-5p was involved in the neuroprotective effect of physical exercise on AD.MethodsA total of 80 AD patients were included,who were divided into an exercise group and matched group.The patients in the exercise group received cycling training with 70%maximum heart rate in the rehabilitation for 3 months.And the patients in the matched group underwent the health education for 3 months and asked to live by the past without aerobic exercise.Serum samples were collected from each participant.8 months old APP/PS1(APPswe/PSENldE9)double Tg mice were purchased as the AD animal model,which were divided randomly into a control group and voluntary exercise group(VE).The mice in the VE group were individually housed in cages with running wheels,to undergo voluntary exercise for 4 weeks,while the mice in the control group were housed individually in cages with immobilized running wheels.After experiments,the hippocampus tissues were collected.RNA extraction and quantitative real-time PCR(qRT-PCR)was used for the measurement of miR-129-5p in the serum or hippocampus tissues.ResultsThe expression levels of miR-129-5P in serum of AD patients in control group and exercise group were compared before and after treatment.The results of qRT-PCR showed that the expression level of miR-129-5p in the control group after treatment had no significant change compared with that before treatment.However,the expression level of miR-129-5p in the exercise group after treatment was significantly higher than that before treatment(P<0.001).In addition,the study also found that before treatment,there was no significantly change in the expression level of miR-129-5p between the exercise group and the control group,while after treatment the expression level of miR-129-5p in the exercise group was significantly higher than that in the control group(P<0.001).In this study,AD mice underwent voluntary exercise on a roller treadmill to simulate aerobic exercise in AD patients.By detecting the expression level of miR-129-5p in AD mice before and after exercise,the effect of exercise on the expression of miR-129-5p was verified.The results of qRT-PCR showed that the expression level of miR-129-5p in the hippocampal tissues of the exercise group was significantly higher than that of the control group.ConclusionAerobic exercise significantly altered the expression level of mir-129-5p in AD patients.Part III Physical exercise affects Alzheimer's disease by regul ating the expression of miR-129-5pObjectivePhysical exercise plays an important neuroprotective role in AD,but the und erlying mechanism remains unclear.This study aimed to explore the molecular m echanism of the protective effect of physical exercise on AD by analyzing the rol e of miR-129-5p in AD mice and patientsMethodsAD mice and patients were respectively treated with 4-week and 3-month ph ysical exercise.Then the serum samples of AD patients and hippocampus tissues were collected for further experiments.qRT-PCR was used to detect the expressio n levels of miR-129-5p in the serum or hippocampus tissues.The psychological s tatus of AD patients was assessed,including MMSE,ADAS-Cog and NPI-Q.The cognitive function of the mice was tested by the Morris water maze test(MW M).The expression levels of related inflammatory factors(IL-1,IL-6,TNF-?)in serum of AD patients and hippocampal tissues of AD model mice were detected by ELISA.ResultsThe present study analyzed the correlation between serum miR-129-5p levels and cognitive function related scores of AD patients.We observed a significant positive correlation between miR-129-5p expression and MMST score(r=0.521,P=0.004),but was negatively correlated with scores of ADAS-cog(r=-0.452,P=0.012)and NPI-Q(r=-0.499,P=0.023).In addition,we further studied the correlation between miR-129-5p and levels of inflammatory factors in patients with AD.It was found that miR-129-5p expression was negatively associated with IL-1?(r=-0.602,P=0.001),IL-6(r=-0.589,P=0.003)and TNF-?(r=-0.651,P<0.001).We further regulated the expression level of miR-129-5p in mice by transfection with miR-129-5p antagomir in vivo.The results showed that after transfection with mir-129-5p antagomir,the expression level of mir-129-5p in hippocampal tissues of AD mice was significantly reduced.The MWM results indicated that the down-regulation of mir-129-5p reversed the protective effect of exercise on learning and cognitive impairment in AD mice,which indicated by the decreased latency to find the hidden platform and distances travelled during the test and increased time spent in the target quadrant and crossings through the original platform location.The ELISA results shown that the relative levels of IL-1?,IL-6 and TNF-?were all reduced by the voluntary exercise(P<0.01).Furthermore,by the knockdown of miR-129-5p in the AD mice,we found that the exercise-induced attenuated IL-1?,IL-6 and TNF-? levels were all elevated(P<0.01).ConclusionDownregulation of mir-129-5p significantly reduced the protective effect of e xercise on cognitive impairment in AD mice.Physical exercise may mediate the neuroinflammatory response in AD mice through regulating miR-129-5p. |
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