Diversity Supplement: Isiah Stephens: Assessing the Role of APOE in Glial Lipid Droplet Metabolism and Function

Abstract Lipid Droplets (LDs) and their associated proteins are known to play a major role in regulating lipid metabolism and storage at the cellular level. Most cell types typically contain some LDs under homeostatic conditions, but excessive accumulation of LDs can be indicative of several pathologies, depending on the tissue. The majority of studies focused on abnormal accumulation of LDs have been conducted in the liver regarding stenosis and non-alcoholic fatty liver disease (NAFLD), or adipose tissue in the context of obesity. However, the accumulation of LDs has also been observed in the brains of individuals with Alzheimer’s Disease (AD), and likely represent the “adipose saccules” in neuroglia first described by Dr. Alois Alzheimer. The expression of a specific LD protein, Perilipin-2 (Plin2), has consistently been shown to correlate with the presence and abundance of LDs within a cell or tissue. Plin2 to is known for being involved in the stabilization of LDs and regulating the access of the LD to enzymes like lipases. Others have shown that modulating the expression of Plin2 directly effects the accessibility and turnover of LDs, where higher levels of Plin2 expression leads to accumulation and little turnover of LDs, and lower levels of Plin2 expression are associated with increased LD turnover and fewer LDs overall. In mice, others have observed alleviation of diet-induced obesity, adipose inflammatory foci, hepatic inflammation, and fibrosis in the liver through the conditional loss of Plin2 in the adipose or liver tissue respectively. One study in particular shows that Plin2-/- mice given a cuprizone- induced demyelinating diet have significantly increased levels of remyelination following the return to a normal diet, and macrophages derived from these mice had fewer lipid droplets and displayed a less inflammatory phenotype. To our knowledge, no studies have targeted neuroglia with a conditional Plin2 KO which leads us to question how the loss of Plin2 would affect lipid droplet accumulation and dysregulated lipid metabolism observed in aging and neurodegeneration. This is a key knowledge gap to understanding lipid metabolism in AD which we hope to bridge through our proposed aims. Specifically, we hypothesize that a reduction in Plin2 expression will alleviate several pathologies associated with AD by increasing LD turnover and decreasing neuroinflammation. We will first generate novel cell-specific Plin2 KO mice that we will then cross with 5xFAD mice to specifically remove Plin2 from either astrocytes or microglia and determine the effects of Plin2 on AD. Then we will investigate how the removal of Plin2 effects phagocytosis activity within microglia and either capacity to clear unwanted debris. Lastly, we will determine the role that Plin2 plays on impairments commonly seen in cells carrying APOE4, the greatest genetic risk factor for late-onset AD.