1. Ldl-stimulated microglial activation exacerbates ischemic white matter damage.
- Author
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Zhou, Luo-Qi, Chu, Yun-Hui, Dong, Ming-Hao, Yang, Sheng, Chen, Man, Tang, Yue, Pang, Xiao-Wei, You, Yun-Fan, Wu, Long-Jun, Wang, Wei, Qin, Chuan, and Tian, Dai-Shi
- Subjects
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WHITE matter (Nerve tissue) , *MICROGLIA , *BLOOD-brain barrier , *PHAGOCYTOSIS , *MYELIN , *DYSLIPIDEMIA - Abstract
• BBB damage is a sustained trigger for demyelination during white matter ischemia. • Vessel-adjacent microglia co-activated by myelin and plasma LDL in white matter ischemia. • LDL-stimulated vessel-adjacent microglia showed compromised microglial regenerative properties. • Lowering circulating LDL may show therapeutic potentials in white matter ischemia. The role of microglia in triggering the blood–brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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