Epigenetic Regulation of Stress-Related Genes in Dementia Brains: A Study R L

Harris, Rachel Laura (2025) Epigenetic Regulation of Stress-Related Genes in Dementia Brains: A Study R L. Masters by Research thesis (MPhil), Manchester Metropolitan University.

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Abstract

Dementia, particularly Alzheimer's disease (AD), is a prevailing cause of cognitive decline worldwide and presents a growing public health and economic burden. The underlying mechanisms of dementia are not fully understood, though they are believed to be multifactorial. Epigenetics, particularly DNA methylation, has gained attention for its involvement in neurodegenerative diseases, with alterations in key stress-related genes being implicated. Chronic stress and elevated cortisol levels, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, are strongly associated with both depression and dementia. Depression is a widely recognised risk factor for dementia, with overlapping pathophysiological features such as neuroinflammation, glucocorticoid dysregulation, and amyloid-beta (Aβ) accumulation. However, the epigenetic link between depression and dementia remains underexplored. This study aimed to investigate the relationship between DNA methylation in stress-related genes Glucocorticoid Receptor (coded by NR3C1) FKBP Prolyl Isomerase 5 (coded by FKBP5) and the Mineralocorticoid Receptor (coded by NR3C2) and cortisol levels, sleep quality and depression in individuals with dementia. Specifically, it sought to determine whether methylation levels in these genes correlate with the longitudinal factors, offering insights into the epigenetic mechanisms that might connect chronic stress and dementia. We conducted an epigenetic analysis on 125 post-mortem frontal cortex brain samples from dementia and healthy patients. DNA methylation levels were measured in key CpG sites within the promoter regions of NR3C1, FKBP5, and NR3C2 genes using bisulfite pyrosequencing. Longitudinal data was collected by University of Manchester Longitudinal Ageing Study for depression, that was assessed through longitudinal depression scores, salivary cortisol and sleep measures obtained through self-reported sleep diaries. Statistical correlations were performed between methylation and cortisol levels, sleep quality and depression to investigate potential associations. Significant correlations were observed between methylation levels and cortisol levels, sleep quality and depression measures. NR3C1 and NR3C2 showed multiple significant relationships with both sleep quality and cortisol levels vs methylation. Depression showed significant relationships with NR3C1, FKBP5 and NR3C2 methylation. No gene‑level differences emerged between neuropathologically defined dementia and control brains. This study has identified multiple statistically significant relationships between the epigenetic regulation of stress-related genes and sleep, cortisol and depression which aligns with the supporting literature. Taken together, these findings suggest that site‑specific methylation changes in HPA‑axis receptors accumulate alongside decades‑long alterations in cortisol rhythm, sleep quality and mood, potentially coupling chronic stress to neurodegeneration. Stress plays a significant role in dementia and a comprehensive understanding of its molecular mechanisms are crucial for disease management through lifestyle modifications, stress management, or pharmacological interventions.