LDL-stimulated microglial activation exacerbates white matter damage

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion are unclear. Here we show that the vessel-adjacent microglia, that being specifically activated by plasma low-density lipoprotein (LDL) leakage during white matter damage, could induce demyelination and attenuate BBB integrity. We further show that LDL stimulation enhance microglial phagocytosis, resulting in over-engulfment of myelin debris, and overwhelming lipid metabolism balance in microglia. Unexpectedly, LDL-stimulated lipid-laden microglia exhibit a total suppressed profile of inflammatory responses, and compromised pro-regenerative properties. Overall, our study demonstrates that LDL-stimulated perivascular microglia show a particular disease-related molecular signature, characterized by suppressed regenerative properties, that is associated with the propagation of demyelination during white matter ischemia. Overall design: Transcriptional profiles of naive microglia and microglia under myelin debris stimulation with or without LDL supplementation. Transcriptional profiles of OPCs co-cultured with naive microglia and microglia under myelin debris stimulation with or without LDL. Transcriptional profiles of endothelial cells co-cultured with naive microglia and microglia under myelin debris stimulation with or without LDL supplementation supplementation