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

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.

Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer’s Dementia Patients: Results of a Preliminary Clinical Trial

“…Little is known about the mechanisms relating gamma stimulation to circadian rhythms. One month of daily hour-long 40 Hz visual stimulation rescues central clock gene expression deficits present in AD mouse models, including CLOCK, BMAL1, and PER2, suggesting 40 Hz stimulation could directly impact the suprachiasmatic nucleus (SCN) (the site of the circadian pacemaker in mammals) and underlying circadian rhythms (Yao et al 2020). These genes are critical regulators of the circadian system and are posited to explain age and disease related patterns in activity levels.…”

Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease

“…40‐Hz stimulation in mouse models also exerts secondary benefits to other systems, including neuroimmune signalling and circadian function, and appears to be even more beneficial when applied simultaneously with exercise [102–104]. One month of daily hour‐long 40‐Hz light flicker rescues central clock gene expression deficits present in APP/PS1 mice, including CLOCK, BMAL1 and PER2, suggesting that gamma stimulation could be having a direct impact on the suprachiasmatic nucleus and underlying circadian rhythms [102].…”

Intermittent Light Exposures in Humans: A Case for Dual Entrainment in the Treatment of Alzheimer's Disease

“…In a healthy brain, microglia exercise a protective function that restrains the accumulation of Aβ and may prevent neurodegeneration ( 122 ). It has been hypothesized that resynchronization of gamma oscillations stimulates recruitment of microglia ( 59 , 123 ) which take part in ridding the central nervous system of undesirable features such as dysfunctional neurons or amyloid plaques ( 124 ). If proven to be viable, harnessing the maintenance role of microglia would be revolutionary, as it would permit the reduction of plaque accumulation using endogenous processes and thereby avoid the introduction of foreign substances to the body.…”

“…In the only publication investigating the impact of an intermittent light at 40 Hz on both circadian clock genes and gamma entrainment, Yao et al ( 123 ) compared mRNA levels of clock genes (BMAL1, Per2, and Clock) before and after exposure to 40 Hz flickering light using an AD mouse model (APP/PS1). They showed that 40 Hz flicker increased gamma in the visual cortex, decreased Aβ deposition, and decreased protein expressions of APP and phosphorylated tau in the hippocampus.…”