CHARACTERIZING FUNCTION OF FAT AND FOAM IN GLIAL CELLS: AGING, INJURY AND NEURODEGENERATION

Lipid droplets (LDs) are emerging as dynamic regulators of cellular metabolism and immune function in the central nervous system, with implications extending across aging, injury, and neurodegenerative disease. This thesis investigates how LD accumulation in glial cells—particularly microglia and astrocytes—transforms from a protective lipid-buffering state ("fat") to a pathological, inflammatory phenotype ("foam"). This work delineates the mechanisms and consequences of glial lipid droplet dysregulation, offering a unifying framework for understanding glial dysfunction in diverse neuropathological contexts.

In the context of Alzheimer’s disease (AD), LD-laden microglia exhibit impaired amyloid-beta (Aβ) phagocytosis and accumulate in plaque-rich regions. Mechanistic experiments reveal that exposure to Aβ induces a shift in microglial lipid metabolism via activation of diacylglycerol acyltransferase 2 (DGAT2). Degradation of DGAT2 in aged 5xFAD mice significantly reduced microglial LD burden, and attenuated plaque load and neuritic dystrophy in vivo, supporting DGAT2 as a therapeutic target for reversing foam-like microglial dysfunction in late-stage AD​. In the aging brain, mitochondrial dysfunction and impaired lipid turnover drive progressive LD accumulation in glial cells, fostering metabolic stress and proinflammatory signaling. In models of spinal cord injury, rapid lipid influx and oxidative damage trigger robust glial LD formation. While initially protective, chronic LD persistence disrupts phagocytosis and contributes to sustained neuroinflammation. Astrocyte-specific deletion of Ccn1, a secreted matricellular protein, further impairs lipid metabolism and debris clearance in white matter injury, underscoring the importance of astrocyte–microglia crosstalk in regulating LD dynamics​. Methodologically, the thesis integrates multiple reaction monitoring (MRM), liquid chromatography-tandem mass spectrometry (LC-MS/MS), and ozone electrospray ionization (OzESI) to provide structural and quantitative resolution of neutral lipid species and their isomers.

Collectively, this work advances a lipid-centric framework for studying glial biology in aging and disease. It demonstrates that LD accumulation is not merely a byproduct of dysfunction but a modifiable node that actively shapes glial responses to stress, damage, and degeneration. The "Fat-to-Foam" model presented here provides conceptual and experimental foundations for understanding glial transitions in neurodegeneration and opens new avenues for targeted lipid-based interventions in neurological disease.