Abstract While genetic risk factors for Alzheimer’s disease (AD) have been identified, around ninety percent of patients are sporadic cases. Therefore, in this proposal, we seek to understand the molecular mechanisms behind the establishment of sporadic cases of AD. Recently, we have found that a putative epigenetic regulator, PHD finger 15 (PHD15), is a transcriptional repressor of genes regulating inflammation in microglia. Indeed, knockout of Phf15 in mouse microglial cells was sufficient to increase pro-inflammatory mediators and anti-viral genes, of note, including amyloid precursor protein (APP) and complement factors, in the absence of any stimuli. Because the mRNA expression of PHF15 in human and mouse microglia is increased upon healthy aging, we hypothesize that PHF15 epigenetically represses age-induced inflammation in microglia and that failure to up-regulate PHF15 results in neuroinflammation and cognitive decline. To test our hypothesis, we will identify members of the protein complex containing PHF15 by mass-spectrometry using a human microglial cell line that we have established. After confirming protein binding using biochemical assays, we will perform functional assays by establishing gain- and loss-of-function cell lines to validate whether the identified complex proteins cooperate with PHF15 to repress inflammation. In addition to isolating the PHF15 protein complex, we will also try to identify non-genetic factors that prevent PHF15 mRNA up-regulation using both in vivo and in vitro models. Based on our preliminary data, we will focus on virus infection and high-fat diet for the in vivo experiments, as well as oxidative stress and infection mimics (ligands for toll-like receptors and inflammasomes) for the in vitro experiments. Overall, the goals of this proposal are to determine the molecular mechanism behind how PHF15 represses inflammation in microglia and to identify non-genetic factors that prevent up-regulation of PHF15 expression. These results may help us to better understand the causes of sporadic cases of AD and, thus, direct the development of treatment strategies to treat and/or prevent this disease.