Presentation description

Alzheimer's (AD) is a debilitating neurodegenerative disease that affects more than 55 million people worldwide. Recent studies have shown that metabolic factors greatly affect the development and progression of AD. Additionally, epigenetic changes to gene regulation have been implicated in the pathogenesis of AD. Thus, we hypothesize that subsets of enhancers, distal regulatory non-coding DNA regions, can be altered by metabolic changes, therefore, altering gene expression related to AD. To test this hypothesis, we are comparing enhancer activity in varying metabolic conditions (fed, fasted, and refed) in C57BL/6J mice and stages of AD in the 5xFAD mouse model (two, five, and nine months), focusing on the hypothalamus, a brain region that regulates metabolism and shows AD pathology. We are utilizing the sequencing assay Cleavage Under Target And Release Using Nuclease (CUT&RUN) to identify changes to poised enhancer activity as indicated by the histone mark H3K4me1 in hypothalami from all previously mentioned conditions. We are also optimizing CUT&RUN for use in frozen hypothalami which is complicated by size, tissue type, and nuclei fragility. Upon completion, these results will be combined with data from other genomic assays indicating chromatin accessibility, contacts between enhancers and genes, and other histone mark indications of enhancer activity. Combined, this will allow us to detect novel enhancer activity linking AD and metabolic states. This information would allow us to identify pathways promoting or deterring the pathogenesis of Alzheimer's and potentially help identify new prevention routes and therapeutic approaches.