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Epigenetic Regulation of BMAL1 in Alzheimer’s Disease Linking Neuropathology, Cognitive Decline and Sleep Quality

Hulme, Bethany (2020) Epigenetic Regulation of BMAL1 in Alzheimer’s Disease Linking Neuropathology, Cognitive Decline and Sleep Quality. Masters thesis (MSc), Manchester Metropolitan University.

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Abstract

Introduction: Alzheimer’s disease (AD) is a neurodegenerative condition that is prevalent in today’s society and is on the rise. A disturbance of the circadian rhythm is an early symptom and is associated with disrupted sleep/wake cycles. CLOCK genes, important in regulating the circadian rhythm, have been hypothesised to regulate important factors in neurodegeneration. These CLOCK genes control circadian timekeeping by regulating their own expression over 24hours via a series of interacting positive & negative feedback loops; with BMAL1 being a key gene that drives the circadian cycle. Sleep disturbances are observed in AD and the reasons for this may be multifactorial and involve beta-amyloid (Aβ), light exposure and sleep disordered breathing (SDB), which are all related to the circadian cycle. Circadian dysfunction is hypothesised to contribute to AD pathogenesis and previous studies show a link between the circadian clock, AD neuropathology, sleep regulation and cognition; particularly fluid intelligence, processing speed, memory and vocabulary. However, it is unclear if circadian dysfunction within AD is causal or consequential to the development of neuropathology. Aim: To investigate if BMAL1 methylation is epigenetically regulated in brains in relation to AD neuropathology, longitudinal changes in cognition, sleep quality and depressive symptoms. This study is designed to assess the hypothesis that BMAL1 methylation will directly affect neuropathology, cognition, sleep quality and depression. Methods: Prefrontal cortex (n=96) samples were acquired from Manchester Brain Bank. DNA methylation at six individual CpG sites on BMAL1 was determined using bisulphite pyrosequencing that was statistically tested for associations with AD neuropathology, longitudinal changes in cognition, sleep quality and depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (F (1, 92)=6.1, p=0.015) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r=0.20, p=0.05) and CpG4 (r=0.20, p=0.05) positively correlated with vocabulary. When testing for age-adjusted cross-sectional data, CpG2 positively correlated with cross-sectional fluid intelligence (r=0.20 p=0.05) and vocabulary (r=0.22 p=0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B=0.03, 95%CI=0.00/0.06, p=0.03) and CpG5 (B=0.04, 95%CI=0.01,0.07, p=0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B=-0.27, 95%CI=0.49/-0.05, p=0.02). Discussion: The results of this study indicate that DNA methylation of BMAL1 is positively associated with AD neuropathology, longitudinal changes in cognition, sleep quality and depression; suggesting that the circadian cycle plays a linking role in regulating these key factors in the development of AD. Further research is needed to understand the dynamics of this relationship.

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