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LDL-stimulated microglial activation exacerbates white matter damage

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE229456 | GEO | 2025/04/12

REPOSITORIES: GEO

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Project description:Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia after Alzheimer’s disease (AD). Currently, the mechanistic insights into the evolution and progression of VCID remain elusive. White matter change represents an invariant feature. Compelling clinical neuroimaging and pathological evidence suggest a link between white matter changes and neurodegeneration. Our prior study detected hypoperfused lesions in mice with partial deficiency of endothelial nitric oxide (eNOS) at very young age, precisely matching to those hypoperfused areas identified in preclinical AD patients. White matter tracts are particularly susceptible to the vascular damage induced by chronic hypoperfusion. Using immunohistochemistry, we detected severe demyelination in the middle aged eNOS-deficient mice. The demyelinated areas were confined to cortical and subcortical areas including the corpus callosum and hippocampus. The intensity of demyelination correlated with behavioral deficits of gait and associative recognition memory performances. By Evans blue angiography, we detected blood-brain barrier (BBB) leakage as another early pathological change affecting frontal and parietal cortex in eNOS-deficient mic. Sodium nitrate fortified drinking water provided to young and middle aged eNOS-deficient mice completely prevented non-perfusion, BBB leakage, and white matter pathology, indicating that impaired endothelium-derived NO signaling may have caused these pathological events. Furthermore, genome-wide transcriptomic analysis revealed altered gene clusters most related to mitochondrial respiratory pathways selectively in the white matter of young eNOS-deficient mice. Using eNOS-deficient mice, we identified BBB breakdown and hypoperfusion as the two earliest pathological events, resulting from insufficient vascular NO signaling. We speculate that the compromised BBB and mild chronic hypoperfusion trigger vascular damage, along with oxidative stress and astrogliosis, accounting for the white matter pathological changes in the eNOS-deficient mouse model. We conclude that eNOS-deficient mice represent an ideal spontaneous evolving model for studying the earliest events leading to spontaneous white matter changes, which will be instrumental to future therapeutic testing of drug candidates and for targeting novel/specific vascular mechanisms contributing to VCID and AD.

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LDL-stimulated microglial activation exacerbates white matter damage

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