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Exosomal miR-532-5p induced by long-term exercise rescues blood–brain barrier function in 5XFAD mice via downregulation of EPHA4 |
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| Authors: | Xiaoyan Liang Wenxin Fa Nan Wang Yuanming Peng Cuicui Liu Min Zhu Na Tian Yongxiang Wang Xiaolei Han Chengxuan Qiu Tingting Hou Yifeng Du |
| Institution: | 1. Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China;2. Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China;3. Department of Clinical Laboratory, Third Hospital of Jinan, Shandong, China;4. Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China Shandong Provincial Clinical Research Center for Neurological Diseases, Jinan, Shandong, China;5. Department of Neurology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China Aging Research Center and Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Stockholm University, Solna, Sweden |
| Abstract: | The breakdown of the blood–brain barrier, which develops early in Alzheimer's disease (AD), contributes to cognitive impairment. Exercise not only reduces the risk factors for AD but also confers direct protection against cognitive decline. However, the exact molecular mechanisms remain elusive, particularly whether exercise can liberate the function of the blood–brain barrier. Here, we demonstrate that long-term exercise promotes the clearance of brain amyloid-β by improving the function of the blood–brain barrier in 5XFAD mice. Significantly, treating primary brain pericytes or endothelial cells with exosomes isolated from the brain of exercised 5XFAD mice improves cell proliferation and upregulates PDGFRβ, ZO-1, and claudin-5. Moreover, exosomes isolated from exercised mice exhibit significant changes in miR-532-5p. Administration or transfection of miR-532-5p to sedentary mice or primary brain pericytes and endothelial cells reproduces the improvement of blood–brain barrier function. Exosomal miR-532-5p targets EPHA4, and accordingly, expression of EphA4 is decreased in exercised mice and miR-532-5p overexpressed mice. A specific siRNA targeting EPHA4 recapitulates the effects on blood–brain barrier-associated cells observed in exercised 5XFAD mice. Overall, our findings suggest that exosomes released by the brain contain a specific miRNA that is altered by exercise and has an impact on blood–brain barrier function in AD. |
| Keywords: | Alzheimer's disease blood–brain barrier exercise exosome miR-532-5p |