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. 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