Knockout of Perilipin-2 in Microglia Alters Lipid Droplet Accumulation and Response to Alzheimer’s Disease Stimuli

Lipid droplets (LDs) are emerging as critical regulators of cellular metabolism and inflammation, with their accumulation in microglia linked to aging and neurodegeneration. Perilipin 2 (Plin2) is a ubiquitously expressed LD-associated protein that stabilizes lipid stores, and in peripheral tissues its upregulation promotes lipid retention, inflammation, and metabolic dysfunction. However, the role of Plin2 in brain-resident microglia remains undefined. Here, we used CRISPR-engineered Plin2 knockout (KO) BV2 microglia to investigate the contribution of Plin2 to lipid accumulation, bioenergetics, and immune function. Compared to wild-type (WT) cells, Plin2 KO microglia exhibited markedly reduced LD burden under both basal and oleic acid–loaded conditions. Functionally, this was associated with enhanced phagocytosis of zymosan particles, even after lipid loading, indicating improved clearance capacity in the absence of Plin2. Transcriptomic analyses revealed genotype-specific responses to amyloid-β (Aβ), particularly in pathways related to mitochondrial metabolism. Seahorse assays confirmed that Plin2 KO cells adopt a distinct bioenergetic profile, with reduced basal respiration and glycolysis but preserved mitochondrial capacity, increased spare respiratory reserve, and a blunted glycolytic response to Aβ. Together, these findings identify Plin2 as a regulator of microglial lipid storage and metabolic state, with its loss alleviating lipid accumulation, improving phagocytic function, and altering Aβ-induced metabolic reprogramming. Targeting Plin2 may therefore represent a potential strategy to modulate microglial metabolism and function in aging and neurodegeneration.