INVESTIGATING THE EFFECTS OF MENOPAUSE-INDUCED EPIGENETIC MECHANISMS IN THE BRAIN

点击翻译按钮获取中文摘要

ABSTRACT More than 100 million people worldwide are estimated to be living with dementia in 2050. Age and sex are the two most important factors determining Alzheimer’s disease (AD) incidence, with women’s lifetime risk double that of men. As women live longer, the total number of women with AD substantially outnumbers men, making the discovery of the molecular links between sex, age, and AD of the greatest significance. One hypothesis for the higher prevalence of AD in women lies in the drastic changes in sex hormones women experience as they traverse menopause, resulting in a depletion of estrogen and progesterone and metabolic changes. Altered metabolism and increased deposition of Amyloid-β begins in peri-menopause and is accompanied by epigenetic modifications, including histone acetylation, which impact on many critical pathways including mitochondrial function. Women also have lower mitochondrial function in brain tissue than males, while new data from our lab demonstrates that sexual dimorphism is observed in cognition and glucose metabolism in an aged AD mouse model. Several reports have made epigenetic modification of histone proteins by histone acetyl transferases (HATs) and histone deacetylases (HDACs) attractive drug targets in AD research. Our lab has shown that HDAC inhibition improves memory in murine models of AD, simultaneously normalizing AD-pathology related molecular changes (e.g. Aβ). To study the sequence of events I propose to utilize a murine model of AD and controlled onset menopause to study epigenetic modifications, metabolism and AD-associated molecular changes that occur during the onset and established ovarian failure. I hypothesize that both histone and non-histone acetyl- group modifications occur during menopause resulting in metabolic dysfunction and acceleration of AD pathology. I will identify acetylation and metabolic changes occurring during peri- and post-menopause-like states in a murine model. These studies will aid in our understanding of the relationship between female sex and AD with the long-term goal to help develop more personalized and/or sex-specific treatments by developing evidence that there is a need for future drug trials to stratify AD patients based on sex.