在阿尔茨海默病动物模型中，自愿性轮转跑步运动可改善睡眠障碍、昼夜节律紊乱和神经病理学。

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

作者信息

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

机构信息

Key Laboratory of Liaoning Province for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

Department of Neurology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

出版信息

Alzheimers Dement. 2025 Jun;21(6):e70314. doi: 10.1002/alz.70314.

DOI:10.1002/alz.70314

PMID:40556345

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12187974/

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/PS1 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.

摘要

引言

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，运动对AD患者的睡眠障碍是否有益尚不清楚。

方法

我们在AD动物模型（APP/PS1小鼠）中进行了为期2个月的自愿轮转跑步（VWR）运动（Ex）。我们评估了行为昼夜节律、睡眠结构、昼夜节律时钟基因、认知功能以及视交叉上核（SCN）、海马体和皮质中的神经退行性变。

结果

在AD小鼠中进行VWR运动后，快速眼动睡眠增加了89%。通过免疫荧光染色，SCN中昼夜节律时钟基因的水平发生了显著变化（脑和肌肉芳香烃受体核转运蛋白样蛋白1 [BMAL1] 和视黄酸受体相关孤儿受体α [RORα] 分别降低了45.7%和36.4%，逆转录红细胞增多症病毒α [REV-ERBα] 增加了119%），在下丘脑的Zeitgeber时间1时，mRNA水平也有明显改变（Bmal1和Rorα分别下降了57%和68%，Rev-erbα升高了79%）；SCN中磷酸化tau 231（p-tau231）降低了35%，而囊泡GABA转运体（VGAT）升高了38.7%。此外，海马体和皮质中的离子钙结合衔接分子1（Iba1）、胶质纤维酸性蛋白（GFAP）、淀粉样β蛋白（Aβ）和p-tau231显著减少。

讨论

我们的结果表明，VWR运动可改善AD小鼠的睡眠障碍、认知缺陷和神经病理学。

要点

自愿轮转跑步（VWR）运动改善了阿尔茨海默病（AD）小鼠的行为昼夜节律紊乱和睡眠结构障碍。VWR运动后，昼夜节律时钟基因的表达水平发生了显著变化，视交叉上核（SCN）中γ-氨基丁酸（GABA）能神经元的tau磷酸化和轴突损伤明显减少。AD小鼠在VWR运动后，下丘脑中β-位点淀粉样前体蛋白裂解酶1（BACE1）和糖原合酶激酶-3β（GSK3β）的水平降低。此外，VWR运动减轻了海马体和皮质中的认知缺陷、神经炎症、淀粉样β蛋白（Aβ）和磷酸化tau蛋白的积累。