Travis Tabor
Program: Neurosciences
Current advisor: David M. Holtzman, MD
Undergraduate university: Appalachian State University
Research summary
It is becoming apparent that changes in glial activities and inflammation play important roles in the progression of Alzheimer’s disease (AD), and many transcriptional analyses have shown that microglia adopt a variety of cell states in brain diseases. In AD brains and mouse models of amyloidosis, tauopathy, and aging, multiple groups have observed interesting myeloid subtypes that accumulate material labeled by neutral lipid stains and is often classified as lipid droplets (LDs). Early characterizations of these microglia containing ‘LDs’ have found that these cells tend to have deficits in phagocytosis and exacerbated responses to inflammatory stimuli; however, the exact roles of microglial LD biogenesis in mammalian in vivo models of neurodegeneration have not yet been fully elucidated.
LDs are ubiquitous organelles with various functions depending on the cell-type and biological context. In many cases, LDs protect cells from lipid stress and oxidative damage by sequestering free fatty acids and cholesterol. We hypothesize that in the context of tauopathy, LDs would have similarly protective roles by allowing microglia to effectively process the lipid-rich debris generated by the disease. To evaluate this hypothesis, we modulated the functional expression of the rate-limiting triglyceride synthesis enzymes DGAT1 and 2 selectively within microglia of the PS19 mouse model of tauopathy and characterized the effects on disease progression using a combination of imaging, lipidomic, and single nucleus RNA sequencing assays. Conditional microglial KO of both DGAT enzymes in adult male PS19 mice resulted in several behavioral deficits, exacerbated hippocampal loss and ventricular dilation, and increased accumulation of CD68+ endolysosomes. Interestingly, neutral lipid-accumulating myeloid cells were more abundant in the PS19 DGAT KO mice relative to controls and much of the lipidic material appeared to be inside or directly adjacent to CD68+ endolysosomal vesicles but not clearly associated with LD surface protein markers. While we are still analyzing several important endpoints, conditionally overexpressing DGAT1 within microglia appeared to protect PS19 mice from a hyperactive behavioral phenotype but did not clearly rescue memory deficits or have statistically significant effects on reducing neurodegeneration. Our studies suggest that microglial DGAT-dependent TAG/LD biogenesis may be a moderately adaptive response to lipid stress in mammalian tauopathy but may not correspond to the bulk of the neutral lipid material that accumulates inside brain myeloid cells which has important implications for the development of lipid-targeting therapies for AD and related conditions.
Graduate publications
Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. 2024 APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell, 187(2):428-445.e20.
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.
Lee J, Dimitry JM, Song JH, Son M, Sheehan PW, King MW, Travis Tabor G, Goo YA, Lazar MA, Petrucelli L, Musiek ES. 2023 Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice. Nat Commun, 14(1):5197.
Litvinchuk A, Suh JH, Guo JL, Lin K, Davis SS, Bien-Ly N, Tycksen E, Tabor GT, Remolina Serrano J, Manis M, Bao X, Lee C, Bosch M, Perez EJ, Yuede CM, Cashikar AG, Ulrich JD, Di Paolo G, Holtzman DM. 2023 Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron, s0896-6273(23):00804-8.
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.