| Background:According to the latest research,at present,the number of AD patients in the world has reached 47 million,and the number of patients with AD in China has exceeded 9 million.Due to the specificity of diagnosis and medical care,it has become a hotspot and difficulty in basic and clinical medicine researches.Previous studies have found that in the brains of AD patients and transgenic mice,the brain regions associated with memory and cognition atrophy,accompanied by neuronal death and synaptic loss.memantine is the only clinically approved exogenously approved by the FDA as glutamate receptor antagonists.in AD brain,different forms of Aβ can directly bind to synaptic myelin and other structures,chemical and electrical signaling between toxic synapses.Glutamate neuron receptors NMDA and AMPA are the mediator mechanism responsible for this change which is highly correlated with the production of postsynaptic membrane LTP.Known as a benign intervention,exercise can increase the expression of BDNF,promote neurogenesis in the hippocampus,regulate the homeostasis of Aβ through various pathways,and whether exercise can regulate the expression of glutamate receptors to achieve exercise-induced synaptic restructure and with the adjustment of synaptic plasticity,more research is needed.Methods:In this experiment,24 APP/PS1 transgenic mice(3 month)and 24 littermate wild control mice were selected and divided into 4 groups,which were wild type control group(WTC,n=12)and wild type exercise group(wild type exercise,WTE,n=12),transgenic control group(ADC,n=12)and transgenic exercise group(ADE,n=12).Before the start of formal exercise intervention,the mice of exercise groups were trained for 3 continuous days,and the speed and exercise lasting time of the running platform were gradually adjusted according to their adaptation.In the formal training stage,the detail exercise protocol as follow: 5 days a week,45 minutes a day,the running speed is set to 13.5m/min,the intensity is about the aerobic exercise intensity of the mouse,the training time is fixed between 17:00-19:00,the exercise intervention lasts for 12 weeks,and the feeding and exercise process of the mice are all under the requirements of ethical standards for laboratory animals.After the 12-week exercise intervention,the classic MWM water maze test was performed at the 13 th week to test the spatial learning and memory ability of each group.The hippocampus tissue of the mice was taken and the electron microscopy tissue sections were prepared.The electron microscopy was used to observe the synapse structure images.The number of synapses in the hippocampal CA1 area and the parameters related to synaptic function and results were analyzed by using the analysis software.The content of Aβ in hippocampal tissue was detected by ELISA experiment.Real-time-PCR was used to detect the transcriptional expression levels of MAP2,NCAM,NR2 B,GluR1,CaMKII genes in hippocampus.Western Blot was used to detect the expression levels of synaptic plasticity-related proteins MAP2,NCAM and glutamate receptor subunits NR2 B,GluR1 and CaMKII in hippocampus.Results:(1)Compared with the WTC group,the indexes related to spatial learning and memory ability in the water maze test of WTE and ADC groups showed significant changes(p<0.05);after 12 weeks of treadmill exercise,each of the ADE groups compared with the ADC group,the index showed significant changes(p<0.05): the escape latency of the navigational experiment was shortened,and the percentage of swimming time of the platform phenomenon increased.The percentage of swimming time of the target platform increased in the space exploration experiment,and the number of crossing the platform increased.(2)Compared with WTC group,the contents of Aβ40 and Aβ42 in hippocampus of ADC group were significantly increased(p<0.01).After 12 weeks of treadmill exercise,the contents of Aβ40 and Aβ42 in hippocampus of ADE group were significantly decreased(p<0.01).(3)Compared with the WTC group,the number of synapses in the hippocampal CA1 region of the WTE group was significantly increased(p<0.05).Compared with the ADC group,the number of synapses in the hippocampal CA1 region of the ADE group was significantly increased(p<0.05);The results of synaptic morphological indicators showed that the length of synaptic PSD in the WTE group was significantly increased compared with the WTC group,and the difference was extremely significant(p<0.01).Compared with the ADC group,the ADE group,the length of the synaptic active region of the mouse was significantly increased(p<0.05).(4)Compared with WTC group,the expression level of MAP2 mRNA in hippocampus of ADC group was significantly decreased(p<0.05).Compared with ADC group,the expression level of MAP2 mRNA in hippocampus of ADE group was significantly increased(p<0.05);compared with WTC group,The expression level of MAP2 protein of WTE group in hippocampus was significantly increased(p<0.05),and the expression level of MAP2 protein in hippocampus of ADC group was significantly decreased(p<0.01).Compared with ADC group,the expression of MAP2 protein in hippocampus of ADE group was significantly increased(p<0.05).Compared with WTC group,the expression of NCAM mRNA in hippocampus of WTE group was significantly increased(p<0.01),and the expression level of NCAM mRNA in hippocampus of ADC group was significantly decreased(p<0.05).Compared with ADC group,the expression of NCAM mRNA in hippocampus of ADE group was significantly elevated(p<0.01);compared with WTC group,the expression of NCAM protein in hippocampus of WTE group was significantly increased(p<0.05).(5)Compared with WTC group,the mRNA expression level of NR2 B subunit in hippocampus of ADC group was significantly decreased(p<0.05);compared with WTC group,the expression level of NR2 B subunit in hippocampus of ADC group was significantly decreased(p<0.01);compared with the ADC group,the NR2 B subunit expression level in the hippocampus of the ADE group was significantly increased(p<0.05).Compared with WTC group,the mRNA expression level of GluR1 subunit in hippocampus of ADC group was significantly decreased(p<0.05);compared with WTC group,the expression level of GluR1 subunit in hippocampus of WTE group was significantly increased(p<0.05),The expression level of GluR1 subunit in hippocampus of ADC group was significantly decreased(p<0.01);compared with ADC group,the expression level of GluR1 subunit in hippocampus of ADE group was significantly increased(p<0.05).Compared with WTC group,the expression of CaMKII mRNA in hippocampus of WTE group was significantly increased(p<0.05),and the expression of CaMKII mRNA in hippocampus of ADC group was significantly decreased(p<0.01).Compared with ADC,the expression of CaMKII mRNA in hippocampus of ADE group was significantly increased(P<0.01);Compared with WTC group,the expression level of CaMKII protein in hippocampus of ADC group was significantly decreased(p<0.01);compared with ADC group,the expression level of CaMKII protein in hippocampus of ADE group was significantly increased(p<0.05).Conclusions:(1)The ability of spatial learning and memory of TgAPP/PS1 mice at 6 months was impaired,while the 12-week treadmill exercise improved spatial cognition.(2)12-week treadmill exercise can reduce the content of Aβ40 and Aβ42 in hippocampus of 6-month-old TgAPP/PS1 mice.(3)12-week treadmill exercise can improve synaptic damage in hippocampal CA1 region of 6-month-old TgAPP/PS1 mice,up-regulate the expression levels of synaptic plasticity-related proteins MAP2 and NCAM,therefore enhance synaptic plasticity regulation.(4)12-week treadmill exercise up-regulated the expression level of glutamate receptor subunit NR2 B,GluR1 and downstream regulatory protein CaMKII in hippocampus of 6-month-old TgAPP/PS1 mice,may promoted synaptic excitability signal transduction. |
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