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

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.