MSTP in PhD Training
Current advisor: David M. Holtzman, MD
Undergraduate university: Appalachian State University, 2016
Enrollment year: 2018
Elucidating roles of microglial lipid droplets in neurodegeneration
Alzheimer Disease (AD) affects approximately 6 million people in the United States and currently has no clearly-effective disease modifying therapies. AD is pathologically defined by the accumulation of amyloid β (Aβ) plaques and tau neurofibrillary tangles in the brain and it is known that alterations in the activities of microglia and other non-neuronal cell types play important roles in shaping the disease course. Much of the polygenic risk for AD is derived from variants in genes expressed by microglia, specifically those involved in endolysosomal and lipid processing pathways, and microglia containing abundant lipid droplets (LD-MG) have been observed in post-mortem human AD brains. As previous interventions targeting Aβ have not yet been successful in clinical trials, the concept of modulating microglial lipid metabolism is a novel and exciting avenue being explored in preclinical studies, however we need to know more about how lipid metabolism governs microglial functional states. In mouse models of amyloidosis, microglia transition from a homeostatic to a disease-associated (DAM) transcriptional state that represents a protective, phagocytic, and plaque-compacting phenotype. While microglial activity may be beneficial in the early amyloid phase of AD, pharmacological or genetic inhibition of microglia has been shown to be protective in mouse models of tauopathy. Given recent evidence suggesting that the LD-MG observed in aged mice have pro-inflammatory, hypo-phagocytic phenotypes, we hypothesize that the LD-MG in AD will have similar pathway alterations and could thus be partially responsible for microglial contributions to neurodegeneration. Our studies will both identify molecular targets amenable for promoting lipid flux in myeloid cells and evaluate the potential of modulating microglial lipid metabolism for the treatment of diseases marked by aberrant lipid metabolism like AD.
Sun R, Han R, McCornack C, Khan S, Tabor GT, Chen Y, Hou J, Jiang H, Schoch KM, Mao DD, Cleary R, Yang A, Liu Q, Luo J, Petti A, Miller TM, Ulrich JD, Holtzman DM, Kim AH. 2023 TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma. Sci Adv, 9(19):eade3559. PMCID: PMC10181199
Huynh TV, Wang C, Tran AC, Tabor GT, Mahan TE, Francis CM, Finn MB, Spellman R, Manis M, Tanzi RE, Ulrich JD, Holtzman DM. 2019 Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model. Mol Neurodegener, 14(1):37. PMCID: PMC6796484