Epigenetic Regulation of Aging and Alzheimer's Disease

McClarty, Bryan

doi:https://doi.org/10.21985/n2-a9aw-1a45

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Epigenetic Regulation of Aging and Alzheimer's Disease

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Aging is the greatest known risk factor for Alzheimer’s Disease (AD); however, the molecular mechanisms underlying aging and how it can initiate and or exacerbate AD, is still unknown. Epigenetic regulation has been widely accepted to play an essential role in aging or AD-related processes; however, whether dysregulations of histone modifications during aging initiate AD is not well understood. This dissertation project addressed this question by using the APP/PS1 transgenic mouse model combined with biochemical and behavioral measures to investigate the class 1 subtypes of histone deacetylases (HDACs) in the modulation of memory and AD-related pathologies in aging and AD. Results showed that class 1 HDACs modulated memory function and AD pathologies in a differential manner. More specifically, results showed HDAC 2 modulated synapse-related gene expression through dysregulations of H3K9ac levels at synapse-related gene promoters during aging and AD in the hippocampus. Conversely, results showed HDAC 3 modulated synapse-related gene expression through dysregulations of H3K9ac levels at synapse-related gene promoters during AD in the prefrontal cortex. For AD pathologies, results showed HDAC 1 and HDAC 3 modulated amyloidosis throughout AD progression and class 1 HDAC’s modulated microglia cell densities. These results helped dissect the dynamic changes of epigenetics that can occur during normal aging and AD provided evidence that indicates dysregulated histone modifications in aging may initiate or exacerbate AD onset and progression. Furthermore, these results helped identify several key epigenetic markers that play a critical role in aging and AD, and these markers could serve as potential future therapeutic targets for AD.

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