{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T14:56:08Z","timestamp":1791557768386,"version":"4.3.4"},"reference-count":57,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32220103006"],"award-info":[{"award-number":["32220103006"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271524"],"award-info":[{"award-number":["82271524"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012476","name":"Fundamental Research Funds for Central Universities of the Central South University","doi-asserted-by":"publisher","award":["YDZX20213100001002"],"award-info":[{"award-number":["YDZX20213100001002"]}],"id":[{"id":"10.13039\/501100012476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>INTRODUCTION<\/jats:title><jats:p>The sleep\u2013wake cycle and circadian rhythm disturbances are common in Alzheimer's disease (AD). However, it is not known if exercise has any benefit for the sleep disorders in AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>We conducted a 2\u2010month voluntary wheel running (VWR) exercise (Ex) in an animal model of AD (APP<jats:sup>SWE<\/jats:sup>\/PS1<jats:sup>dE9<\/jats:sup> mice). We assessed behavioral circadian rhythm, sleep structure, circadian clock genes, cognitive function, and neurodegeneration in the suprachiasmatic nucleus (SCN), the hippocampus, and the cortex.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>After VWR exercise in the AD mice, the rapid eye movement sleep was increased by 89%.\u00a0The levels of circadian clock genes were significantly changed (brain and muscle arnt\u2010like protein 1 [BMAL1] and retinoic acid receptor\u2010related orphan receptors\u03b1 [ROR\u03b1] reduced by 45.7% and 36.4%, reverse erythroblastosis virus\u03b1 (REV\u2010ERB\u03b1) increased by 119%) in the SCN by immunofluorescence staining, with the mRNA levels were markedly altered (<jats:italic>Bmal1<\/jats:italic> and <jats:italic>Ror\u03b1<\/jats:italic> decreased by 57% and 68%, <jats:italic>Rev\u2010erb\u03b1<\/jats:italic> elevated by 79%) in the hypothalamus at Zeitgeber Time 1; phospho\u2010tau 231 (p\u2010tau231) was reduced by 35%, whereas vesicular GABA transporter (VGAT) was elevated by 38.7% in the SCN. In addition, ionized calcium binding adapter molecude 1 (Iba1), glial fibrillary acidic protein (GFAP), amyloid \u03b2 (A\u03b2), and p\u2010tau231 were significantly reduced in the hippocampus and cortex.<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Our results demonstrate that VWR exercise improves sleep disorders, cognitive deficits, and neuropathology in AD mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Voluntary wheel running (VWR) exercise improves the behavioral circadian rhythm disorder and sleep structure disturbance in Alzheimer's disease (AD) mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>After VWR exercise, there is a significant change in the expression levels of circadian clock genes, and a remarkable reduction of tau phosphorylation and axonal damage in the \u03b3\u2010aminobutyric acid (GABA)ergic neurons in the suprachiasmatic nucleus (SCN).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The levels of beta\u2010site amyloid precurson protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase\u20103\u03b2 (GSK3\u03b2) are reduced in the hypothalamus after VWR exercise in AD mice.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Furthermore, VWR exercise attenuates cognitive deficits, neuroinflammation, amyloid beta (A\u03b2), and phospho\u2010tau protein accumulation in the hippocampus and cortex.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.70314","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T01:31:46Z","timestamp":1750815106000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Voluntary wheel running exercise improves sleep disorder, circadian rhythm disturbance, and neuropathology in an animal model of Alzheimer's disease"],"prefix":"10.1002","volume":"21","author":[{"given":"Yiying","family":"Hu","sequence":"first","affiliation":[{"name":"Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases The First Affiliated Hospital of Dalian Medical University  Dalian China"},{"name":"Department of Neurology The First Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Niu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases The First Affiliated Hospital of Dalian Medical University  Dalian China"},{"name":"Department of Neurology Heping Hospital affiliated to Changzhi Medical College  Changzhi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases The First Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijia","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases The First Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhui","family":"Qiu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases The First Affiliated Hospital of Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Dalian Seventh People's Hospital  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Liu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaibin","family":"Cai","sequence":"additional","affiliation":[{"name":"Transgenic Section, Laboratory of Neurogenetics National Institute on Aging National Institutes of Health  Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weidong","family":"Le","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Medicine Shanghai University of Medicine and Health Sciences  Shanghai China"},{"name":"Center for Clinical Research on Neurological Diseases the First Affiliated Hospital Dalian Medical University  Dalian 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