Lipid-induced microglial dysfunction

Lipid-induced microglial dysfunction is a pathological state characterized by the functional impairment of microglia due to the abnormal accumulation or sensing of lipids, such as saturated fatty acids and cholesterol. This condition often manifests as the formation of lipid-droplet-accumulating microglia (LDAM), which exhibit a unique transcriptional profile, defective phagocytic capacity, and increased production of reactive oxygen species and pro-inflammatory cytokines (Marschallinger et al., 2020, Nature Neuroscience). Saturated fats like palmitate can trigger this dysfunction by activating Toll-like receptor 4 (TLR4) and the NLRP3 inflammasome, leading to chronic neuroinflammation (Loving & Bruce, 2020, Frontiers in Immunology). Conversely, the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) acts as a critical lipid sensor; its deficiency or dysfunction impairs the ability of microglia to clear lipid debris, exacerbating neurodegeneration in diseases like Alzheimer's (Nugent et al., 2020, Cell Reports). While not a single molecular target itself, this process is a major focus of therapeutic intervention, with drugs aiming to restore lipid homeostasis through PPAR agonists or TREM2 modulation to mitigate neurotoxic inflammation.

Other names

Microglial lipid overloadLipid-droplet-accumulating microglia (LDAM)Fatty acid-induced neuroinflammationMicroglial lipid metabolic dysfunctionLipid-laden microglia

Modulation of lipid-sensing receptors (e.g., TREM2, TLR4), activation of nuclear receptors to enhance lipid catabolism (e.g., PPARs), or inhibition of the inflammasome pathway to reduce lipid-triggered inflammation.