Voluntary wheel running exercise improves sleep disorder, circadian rhythm disturbance, and neuropathology in an animal model of Alzheimer's disease

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-06-24 DOI:10.1002/alz.70314

Yiying Hu, Long Niu, Yixin Chen, Huijia Yang, Xinhui Qiu, Fei Jiang, Cong Liu, Huaibin Cai, Weidong Le

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Abstract

INTRODUCTION

The sleep–wake 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.

METHODS

We conducted a 2-month voluntary wheel running (VWR) exercise (Ex) in an animal model of AD (APP^SWE/PS1^dE9 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.

RESULTS

After VWR exercise in the AD mice, the rapid eye movement sleep was increased by 89%. The levels of circadian clock genes were significantly changed (brain and muscle arnt-like protein 1 [BMAL1] and retinoic acid receptor-related orphan receptorsα [RORα] reduced by 45.7% and 36.4%, reverse erythroblastosis virusα (REV-ERBα) increased by 119%) in the SCN by immunofluorescence staining, with the mRNA levels were markedly altered (Bmal1 and Rorα decreased by 57% and 68%, Rev-erbα elevated by 79%) in the hypothalamus at Zeitgeber Time 1; phospho-tau 231 (p-tau231) 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 β (Aβ), and p-tau231 were significantly reduced in the hippocampus and cortex.

DISCUSSION

Our results demonstrate that VWR exercise improves sleep disorders, cognitive deficits, and neuropathology in AD mice.

Highlights

Voluntary wheel running (VWR) exercise improves the behavioral circadian rhythm disorder and sleep structure disturbance in Alzheimer's disease (AD) mice.
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 γ-aminobutyric acid (GABA)ergic neurons in the suprachiasmatic nucleus (SCN).
The levels of beta-site amyloid precurson protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β) are reduced in the hypothalamus after VWR exercise in AD mice.
Furthermore, VWR exercise attenuates cognitive deficits, neuroinflammation, amyloid beta (Aβ), and phospho-tau protein accumulation in the hippocampus and cortex.

Abstract Image

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在阿尔茨海默病的动物模型中，自愿轮跑运动改善了睡眠障碍、昼夜节律紊乱和神经病理学

睡眠-觉醒周期和昼夜节律紊乱在阿尔茨海默病（AD）中很常见。然而，尚不清楚运动是否对阿尔茨海默氏症患者的睡眠障碍有任何益处。方法我们在AD动物模型（APPSWE/PS1dE9小鼠）中进行了为期2个月的自愿轮毂跑（VWR）运动（Ex）。我们评估了行为昼夜节律、睡眠结构、生物钟基因、认知功能和视交叉上核（SCN）、海马和皮层的神经变性。结果经VWR运动后，AD小鼠快速眼动睡眠增加89%。免疫荧光染色显示，SCN中生物钟基因水平发生了显著变化（脑肌类蛋白1 [BMAL1]和视黄酸受体相关孤儿受体α [RORα]分别降低45.7%和36.4%，逆转录成红细胞增多症病毒α (REV-ERBα)升高119%），下丘脑在Zeitgeber Time 1时的mRNA水平也发生了显著变化（BMAL1和RORα分别降低57%和68%，REV-ERBα升高79%）；在SCN中，磷酸化tau231 （p-tau231）减少了35%，而水泡状GABA转运蛋白（VGAT）升高了38.7%。此外，在海马和皮质中，离子钙结合适配器分子1 （Iba1）、胶质纤维酸性蛋白（GFAP）、β淀粉样蛋白（Aβ）和p-tau231显著减少。我们的研究结果表明，VWR运动可以改善AD小鼠的睡眠障碍、认知缺陷和神经病理学。自愿轮跑（VWR）运动改善阿尔茨海默病（AD）小鼠的行为昼夜节律障碍和睡眠结构障碍。VWR运动后，大鼠视交叉上核(SCN) γ-氨基丁酸（GABA）能神经元的tau磷酸化和轴突损伤显著减少，生物钟基因表达水平发生显著变化。VWR运动后，AD小鼠下丘脑β -位点淀粉样蛋白前体蛋白切割酶1 （BACE1）和糖原合成酶激酶3β (GSK3β)水平降低。此外，VWR运动可减轻认知缺陷、神经炎症、β淀粉样蛋白（Aβ）和海马和皮层中磷酸化tau蛋白的积累。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.