Epigenetic Regulation of BMAL1 with Sleep Disturbances and Alzheimer’s Disease

Abstract

Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) 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. 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, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = –0.27, 95% CI, p = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.

Defining circadian disruption in neurodegenerative disorders

“…Similarly, the diurnal rhythmic pattern in the expression of the several clock genes was lost in the pineal gland in AD patients (98). Finally, the rhythmic methylation of BMAL1 is disrupted in AD, and this correlates with tau pathology, cognitive disturbance, and overnight wakefulness (99,100). These results support the idea that rhythms in clock gene expression are disrupted in AD patients, but more work in this area is needed.…”

Role of Bmal1 and Gut Microbiota in Alzheimer’s Disease and Parkinson’s Disease Pathophysiology: The Probable Effect of Melatonin on Their Association

“…Additionally, increased methylation of Bmal1 has been observed in frontal cortex tissues of AD patients. In this study, reduced Bmal1 expression has been linked to AD pathology, mainly tau hyperphosphorylation and formation of neurofibrillary tangles . On a molecular level, Bmal1 disruption has been shown to be involved in different aspects of AD pathophysiology, especially Aβ accumulation and neuroinflammation .…”

Dysfunction of circadian and sleep rhythms in the early stages of Alzheimer's disease

“…68 Moreover, BMAL1 methylation is associated with tau pathology, night-waking and depression but not with speed and memory tests, or sleep duration in humans. 97 Melatonin is a circadian clock-regulated hormone secreted by the pineal gland under the control of the SCN as a biological signal for darkness; it has sleep-promoting properties in humans and regulates body temperature. 9 Melatonin has a neuroprotective effect in animal models of AD.…”

“…In mice, specific deletion of BMAL1 in neurons and glia induced oxidative damage and degeneration of synaptic terminals 68 . Moreover, BMAL1 methylation is associated with tau pathology, night‐waking and depression but not with speed and memory tests, or sleep duration in humans 97 …”