Fig. 2: Mechanisms of excessive lipid droplet accumulation and metabolic dysfunction in microglia.
From: Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases
Microglia accumulate excessive lipid droplets (LDs) due to both intrinsic and extrinsic cues. Intrinsic triggers include ER stress, toxic protein aggregates, inflammatory mediators, metabolic stressors (e.g., high glucose, hypoxia), and genetic mutations (e.g., GRN, APOE4), all of which disrupt lipid homeostasis and promote LDs biogenesis. Extrinsic factors such as lipid or LDs transfer from neurons and astrocytes, and possibly peripheral lipids, further exacerbate LDs accumulation. This LDs-laden microglial state is associated with impaired nuclear-cytoplasmic transport (NCT), unresolved DNA damage, and mitochondrial dysfunction characterized by reduced fatty acid oxidation and ATP production. Maybe, as a compensatory response, GLUT1 expression is increased to support glucose uptake. Created with Biorender.com.
