UC San Diego

Alzheimer’s Disease (AD) is a severe neurodegenerative disease characterized by cognitive dysfunction caused by synaptic loss. Its pathogenesis is driven by the development of extracellular plaques due to the accumulation of misfolded amyloid-beta protein and the formation of neurofibrillary tangles (NFTs) caused by the aggregation of misfolded Tau. Due to protein aggregation and cell loss during neurodegeneration, microglia, the innate immune cells of the central nervous system (CNS), acquire a unique activation phenotype that triggers inflammation. My thesis aims to explore the role of DNA methylation in driving these inflammatory responses using human-immortalized microglial cells. We profiled these cells for various inflammatory and disease-associated microglia (DAM) markers following in-vitro exposure to either lipopolysaccharide to model bacterial infections or to amyloid-beta to model neuroinflammation in AD. To investigate global methylation mediating these inflammatory changes, we measured 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) levels at specific time points. We also explored the potential of TET inhibitors as a therapeutic approach to reduce neuroinflammation by measuring the changes in 5-mC and 5-hmC levels as well as inflammatory markers in cells treated with the TET-inhibitor C35. Taken in all, my results suggest that DNA methylation plays an essential role in eliciting the inflammatory response of microglia to different stimuli, thus implicating this epigenetic mechanism in the pathology of AD.