| Background:Alzheimer’s disease (AD) is a neurodegenerative disease, which occurs in the stage of old age and early old age. The pathological characteristics of AD include the impairment of cognitive function, such as decrease in learning and memory, and the loss of speak and sense of direction. AD seriously harms not only the mental health and physical conditions of patients, but also increases economic burden of families and communities. Over the last several decades, a lot of research on treatment for AD has been done, but the prevalence of AD is still out of control. Therefore, the research in prevention or mitigation of AD is very important. Many studies demonstrated that physical activity is an economical and environmental way that promotes not only the physical health, but also brain plasticity. Meanwhile, participating exercise may enhance the recovery of organism from pathological injury and alleviate the pathological changes in central nerve system. Research in humana showed that exercise improves cognitive function and reduce the risk of AD. Animal experiments also supported that exercise improve learning and memory and decrease some pathological changes in AD animals. However, the exact mechanism underlying the effects of exercise on AD remains unknown. The purpose and design of this study were made based on aforementioned knowledge.Objective:APP/PS1 transgenic mice were used in the current study. In the age of 3 months, the transgenic mice were given wheel running exercise, lasting for 16 weeks. Thereby investigating the effects of voluntary exercise on learning and memory and Aβ (β-amyloid) deposition in the hippocampus, the effects of voluntary exercise on generation and cleaving of Aβ in the hippocampus in APP/PS1 transgenic mice. The purpose of the current study is to investigating the potential mechanisms underlying the effects of voluntary exercise on regulation of learning and memory and Aβ deposition in the hippocampus in APP/PS1 transgenic mice.Methods:Thirty-three APP/PS1 transgenic male mice were randomly allocated into transgenic exercise group (TE, n=17) and transgenic control group (TC, n= 17).Thiry-two male wild type C57BL/6 mice were also randomly allocated into wild type exercise group (E, n= 17) and wild type control group (C, n= 17). Among thoese, mice in group TE and group E were undergone wheel running exercise for 16 weeks with normal eating and drinking. At the end of exercise intervention, Morris water maze was used to examine spatial learning and memory in mice from all four groups in the 17th week. Twenty-four hours after the water maze test, all mice in four groups were narcotized and beheaded, and the hippocampus were harvested according to standard experiment protocol and cryopreserved in-80 degrees until analsis. Real-time fluorescence quantitative RT-PCR was used to determine gene transcription level of hippocampal BDNF, NGF, IGF-1, ADAM9, ADAM 10, ADAM17, BACE1, PS1, NEP, IDE, ACE, MMP9, ECE, Plasmin, LRP-1 and RAGE in mice of four groups. Western blot was used to determine protein expression of hippocampal APP, ADAM10, BACE1, PS1, Aβ40, Aβ42, NEP, IDE, ACE, MMP9, LRP-1 and RAGE in mice of four groups. Immunohistochemistry was used to determine hippocampal Aβ deposition in mice of four groups. Congo red staining was used to determine conditions of senile plaque deposition in the hippocampus.Results:(1) Compared with wild-type control group, the latency and path length in Morris water maze was significantly increased, but the time percent, path length percent in platform quadrant and the crossing times across platform were significantly declined in mice of APP/PS1 transgenic control group. But 16 weeks wheel running significantly down-regulated the the latency and path length in Morris water maze, and significantly up-regulated the time percent, path length percent in platform quadrant and the crossing times across platform in Morris water maze in mice of transgenic wheel running group compared with mice in APP/PS1 transgenic control group.(2) Compared with wild-type control group, gene transcription level of hippocampal BDNF, NGF and IGF-1 in mice of APP/PS1 transgenic control group was significantly down-regulated. But 16 weeks wheel running significantly up-regulated gene transcription level of hippocampal BDNF, NGF and IGF-1 in mice of transgenic wheel running group compared with mice in APP/PS1 transgenic control group.(3) Compared with wild-type control group, gene expression level of hippocampal APP, PS1 and BACE1 was significantly increased, while gene expression level of hippocampal ADAM 10 and ADAM 17 was significantly decreased in mice of APP/PS1 transgenic control group. But 16 weeks wheel running significantly inhibited gene expression level of hippocampal APP, PS1 and BACE1, and significantly up-regulated gene expression level of hippocampal ADAM 10 and ADAM 17 in mice of transgenic wheel running group compared with mice in APP/PS1 transgenic control group.(4) Compared with wild-type control group, gene expression level of hippocampal NEP, IDE, ACE and MMP9 was significantly decreased in mice of APP/PS1 transgenic control group. But 16 weeks wheel running significantly up-regulated gene expression level of hippocampal Aβ degradation enzyme NEP, IDE, ACE and MMP9 compared with mice in APP/PS1 transgenic control group.(5) Compared with wild-type control group, gene expression level of hippocampal LRP-1 that brings Aβ out of brain was significantly decreased, while RAGE that brings Aβ into brain was significantly increased in mice of APP/PS1 transgenic control group. But 16 weeks wheel running significantly up-regulated gene expression level of hippocampal LRP-1 and down-regulated hippocampal RAGE mRNA level in mice of APP/PS1 transgenic wheel running group, but there was no significant change in protein expression level of hippocampal RAGE compared with mice in APP/PS1 transgenic control group.(6) Compared with wild-type control group, protein expression level of hippocampal Aβ340 and Aβ42, deposition of Aβ and accumulation of senile plaques were significantly increased in mice of APP/PS1 transgenic control group. But 16 weeks wheel running induced significantly down-regulation in protein expression level of hippocampal Aβ40 and Aβ342, Aβ deposition and senile plaques in mice of transgenic wheel running group compared with mice in APP/PS1 transgenic control group.Conclusions:(1) Spatial learning and memory was significantly impaired in APP/PS1 transgenic mice. But sixteen weeks wheel running significantly ameliorated the special learning and memory in APP/PS1 transgenic AD mice.(2) Expressions of hippocampal nerve factors were significantly decreased in APP/PS1 transgenic mice. But sixteen weeks wheel running increased the expression of hippocampal neural factors in APP/PS1 transgenic AD mice.(3) The β-secretase level in hydrolysis of APP amyloidogenic pathway was significantly increased in APP/PS1 transgenic AD mice, while the a-secretase level in hydrolysis of APP nonamyloidogenic pathway was significantly decreased. But sixteen weeks wheel running up-regulated expression of hippocampal a-secretase, down-regulated expression of hippocampal P-secretase, and down-regulated the level of hippocampal Aβ in APP/PS1 transgenic AD mice.(4) The level of Aβ-degrading enzyme and Aβ transport protein that transport Aβout of the brain were significantly decreased in the hippocampus of APP/PS1 transgenic mice, which led to increase in amyloid plaques. But sixteen weeks wheel running up-regulated the level of Aβ-degrading enzyme and Aβ transport protein in the hippocampus of APP/PS1 transgenic AD mice, increasing the clearance of Aβ, thereby lowering hippocampal deposition of Aβ and accumulation of senile plaques in APP/PS1 transgenic AD mice. |
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