The role of ApoE-mediated microglial lipid metabolism in brain aging and disease

Microglia are a unique population of immune cells resident in the brain that integrate complex signals and dynamically change phenotypes in response to the brain microenvironment. In recent years, single-cell sequencing analyses have revealed profound cellular heterogeneity and context-specific transcriptional plasticity of microglia during brain development, aging, and disease. Emerging evidence suggests that microglia adapt phenotypic plasticity by flexibly reprogramming cellular metabolism to fulfill distinct immune functions. The control of lipid metabolism is central to the appropriate function and homeostasis of the brain. Microglial lipid metabolism regulated by apolipoprotein E (ApoE), a crucial lipid transporter in the brain, has emerged as a critical player in regulating neuroinflammation. The ApoE gene allelic variant, ε4, is associated with a greater risk for neurodegenerative diseases. In this review, we explore novel discoveries in microglial lipid metabolism mediated by ApoE. We elaborate on the functional impact of perturbed microglial lipid metabolism on the underlying pathogenesis of brain aging and disease.