Microglial Perilipin-2 Deficiency Ameliorates Ischemic White Matter Injury via Lipid Metabolic Reprogramming

Background Chronic cerebral hypoperfusion-induced white matter lesions are a major contributor to vascular cognitive impairment in aging, characterized by microglial activation and defective clearance of cholesterol-rich myelin debris. Perilipin-2 (PLIN2), a key lipid droplet (LD)-associated protein involved in myelin metabolism, has an undefined role in ischemic white matter injury. Methods Microglia-specific Plin2 knockout ( Plin2 ^⁻/⁻ ) mice were subjected to bilateral common carotid artery stenosis (BCAS) to model cerebral hypoperfusion. Cognitive function, white matter integrity, and microglial phenotype were assessed. In parallel, integrated microglial transcriptomic and lipidomic analyses were performed to characterize inflammatory states and lipid metabolic profiles. Furthermore, the autophagy inhibitor chloroquine (CQ) was used in vivo and in vitro to test mechanistic dependence on autophagy. Results Plin2 deletion rescued BCAS-induced cognitive and motor deficits, attenuated white matter damage, and promoted remyelination. Plin2 ^⁻/⁻ microglia exhibited enhanced clearance of myelin-derived LDs and a reduced pro-inflammatory state, driven by an upregulation of the autophagy-lysosomal pathway (lipophagy). Crucially, CQ treatment abolished these neuroprotective effects, as evidenced by re-induced LD accumulation, and reinstated inflammatory activation in Plin2 ^⁻/⁻ mice and cultured microglia. Conclusion Microglial Plin2 deletion protects against hypoperfusion injury by enhancing LD clearance, reprogramming lipid metabolism, and suppressing neuroinflammation in an autophagy-dependent manner. Clinically, PLIN2 may represent a promising therapeutic target for ischemic white matter injury and vascular cognitive impairment.