Microglial lipid droplets as therapeutic targets in age-related neurodegenerative diseases

Monoclonal antibodies approved for Alzheimer's disease (AD), such as lecanemab and aducanumab, have been shown to enhance microglial phagocytic function, underscoring the therapeutic relevance of microglia in neurodegenerative diseases (NDDs). Emerging evidence implicates lipid droplets (LDs) in brain aging and NDDs, particularly through LDs-laden microglia known as lipid droplet-accumulating microglia (LDAM), which exhibit impaired phagocytosis, elevated oxidative stress, and dysregulated lipid metabolism. Among microglial subtypes identified through transcriptomic and functional profiling-including disease-associated microglia (DAM), microglia in neurodegenerative disease (MGnD), white matter-associated microglia (WAM), and dark microglia-LDs-laden microglia have clear metabolic signatures defined by excessive LDs accumulation and disrupted lipid turnover. Here, we discuss the biogenesis of LDs, their pathological accumulation in microglia, and the therapeutic potential of targeting LDs. We further propose a hypothetical mechanism by which LDs clearance restore energy metabolism, nuclear transport, facilitate DNA repair, suppress inflammation, and phagocytosis in microglia. Thus, elucidating LDs dynamics in microglia may provide novel therapeutic avenues for modifying the course of NDDs.