Non-invasive 40-Hz Light Flicker Ameliorates Alzheimer's-Associated Rhythm Disorder via Regulating Central Circadian Clock in Mice.

Youli Yao,Shengli Zhang,Zhenglong Lin,Huazhang Zhu,Qiyu Deng,Ying Ying,Yingying Zhao,Junxian Ma,Wenjiang Zhang

doi:10.3389/fphys.2020.00294

Abstract

Alzheimer’s disease (AD) patients often exhibit perturbed circadian rhythm with fragmented sleep before disease onset. This study was designed to evaluate the effect of a 40-Hz light flicker on circadian rhythm in an AD mouse model (APP/PS1). Locomotor rhythms recordings were conducted to examine the circadian clock rhythm in APP/PS1 mice. Molecular biology analyses, including western blot and real-time qPCR assays, were conducted to assess the changes in circadian locomotor output cycles kaput (CLOCK), brain and muscle arnt-like protein-1 (BMAL1), and period 2 (PER2). In addition to determining the direct effect of a 40-Hz light flicker on hypothalamic central clock, whole-cell voltage-clamp electrophysiology was employed to record individual neurons of suprachiasmatic nucleus (SCN) sections. The results reported herein demonstrate that a 40-Hz light flicker relieves circadian rhythm disorders in APP/PS1 mice and returns the expression levels of key players in the central circadian clock, including Clock, Bmal1, and Per2, to baseline. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in SCN neurons is significantly lower in APP/PS1 mice than in the control, and the amplitude of sIPSCs is decreased. Exposure to a 40-Hz light flicker significantly increases the sIPSC frequency in SCN neurons of APP/PS1 mice, with little effect on the amplitude. However, the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) are both unaffected by a 40-Hz light flicker. The data suggest that a 40-Hz light flicker can ameliorate AD-associated circadian rhythm disorders, presenting a new type of therapeutic treatment for rhythm disorders caused by AD.

Highlights

Alzheimer’s disease is a neurogenic disease presenting with dementia
The results reported demonstrate that a 40-Hz light flicker relieves circadian rhythm disorders in APP/PS1 mice and returns the expression levels of key players in the central circadian clock, including circadian locomotor output cycles kaput (Clock), brain and muscle arnt-like protein-1 (Bmal1), and Per2, to baseline
We found that the hypothalami of APP/PS1 mice have a significant reduction of the Bmal1, Clock, and Per2 mRNA levels compared to those of control mice (1 ± 0.13, 1 ± 0.08, and 1 ± 0.28 in the control group and 0.36 ± 0.26, 0.44 ± 0.08, and 0.29 ± 0.15 in the APP/PS1 group, respectively) (Figure 5A)

Summary

Introduction

Alzheimer’s disease is a neurogenic disease presenting with dementia. The main pathological features of AD include the deposition of extracellular amyloid-β (Aβ) plaques and the buildup of intracellular hyperphosphorylated tau and neurofibrillary tangles (NFTs) (Khan et al, 2016). The primary symptoms of AD are severe progressive cognitive deficits, gradual memory loss, and circadian rhythm disturbances. Circadian disturbances have been reported in approximately 45% of AD patients (Saeed and Abbott, 2017), presenting as reduced locomotor activity, fragmented sleep, sundowning syndrome, and disrupted core body temperature (Prinz et al, 1982; Satlin et al, 1995; Bliwise, 2004; Bliwise et al, 2011; Van Erum et al, 2018). Circadian rhythm disturbances may represent preclinical preceding overt cognitive symptoms and memory loss (Carpenter et al, 1996; Moran et al, 2005; Vanderheyden et al, 2018). Recent studies suggest that disrupted circadian rhythms may be a principal component of the causal pathway, leading to AD pathogenesis and progression (Vanderheyden et al, 2018)

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