Andrew Alexander

Introduction.  Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in the world, provoking symptoms such as memory loss, cognitive impairment and disruption of circadian rhythms.^1,2  AD entails the formation of beta-amyloid (Aβ) plaques and tau protein neurofibrillary tangles, both of which have been associated with oxidative stress, a suspected cause of the neurodegeneration in AD.^1,3,4  While originally thought to be merely a symptom of AD, circadian disturbances have become of increased interest in AD research as mechanisms bridging circadian disturbances and AD progression have begun to be discovered.¹  This paper seeks to illustrate how oxidative stress serves as one of these bridges by forming a positive feedback loop between circadian disturbances and AD as well as how it may be used to treat and diagnose AD.  Methods.  Human subjects were subjected to conditions of sleep deprivation and rested wakefulness and given a PET scan for amyloid concentration.⁵  Mice were subjected to circadian disturbance via repeated eight-hour phase advances of the Light:Dark cycle and assessed for changes in oxidative state.⁶  The effects of AD on Bmal1, an essential protein for circadian clock functionality, were assessed by comparing Bmal1 concentration in Aβ-treated cells to control cells, then utilizing gene silencing to determine underlying mechanisms.⁷  DNA methylation changes in Bmal1 were also assessed by performing methylation profiling on cultured fibroblasts and postmortem human frontal cortex samples of AD and control brains.⁸  Results.  Sleep deprivation in humans was found to result in a significant increase in amyloid concentration in the right hippocampus, suggesting an increase in oxidative stress.⁵  Circadian disturbances in mice depleted glutathione reductase, increasing the oxidative state.⁶  Bmal1 was found to be degraded via sumoylation in the presence of Aβ, potentially causing circadian disturbances through an oxidative stress response.⁷  The Bmal1 gene was found to have significant DNA methylation changes in AD, suggesting that oxidative stress from Aβ could also cause circadian disturbances by altering Bmal1 transcription.⁸  Conclusions.  These studies indicate that AD and circadian disturbances have a symbiotic relationship through a positive feedback loop that uses oxidative stress as a bridge that connects the two with various mechanisms, such as AD-produced oxidative stress interfering with clock proteins and circadian disturbances allowing for amyloid buildup and an increased oxidative state that supports oxidative stress-induced neurodegeneration such as that seen in AD.  Targeting these mechanisms may provide a means of treatment and diagnosis for AD.

1. Cronin P, McCarthy MJ, Lim ASP, et al. Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement. 2017;13(6):689–700. doi:10.1016/j.jalz.2016.10.003
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5. Shokri-Kojori E, Wang GJ, Wiers CE, et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018;115(17):4483–4488. doi:10.1073/pnas.1721694115
6. Levault KR, Tischkau SA, Brewer GJ. Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model. J Alzheimers Dis. 2015;49(2):301-316. doi:10.3233/jad-150026
7. Song H, Moon M, Choe HK, et al. Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease. Mol Neurodegener. 2015;10:13. Published 2015 Mar 19. doi:10.1186/s13024-015-0007-x
8. Cronin P, McCarthy MJ, Lim ASP, et al. Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement. 2017;13(6):689–700. doi:10.1016/j.jalz.2016.10.003