Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) accompanied by blood-brain barrier (BBB) disruption. Dysfunction in microglial lipid metabolism is believed to be closely associated with the neuropathology of NMOSD. However, there is limited evidence on the functional relevance of circulating lipids in CNS demyelination, cellular metabolism, and microglial function. Here, we found that serum low-density lipoprotein (LDL) was positively correlated with markers of neurological damage in NMOSD patients. In addition, we demonstrated in a mouse model of NMOSD that LDL penetrates the CNS through the leaky BBB, directly activating microglia. This activation leads to excessive phagocytosis of myelin debris, inhibition of lipid metabolism, and increased glycolysis, ultimately exacerbating myelin damage. We also found that therapeutic interventions aimed at reducing circulating LDL effectively reversed the lipid metabolic dysfunction in microglia and mitigated the demyelinating injury in NMOSD. These findings shed light on the molecular and cellular mechanisms underlying the positive correlation between serum LDL and neurological damage, highlighting the potential therapeutic target for lowering circulating lipids to alleviate the acute demyelinating injury in NMOSD.

视神经脊髓炎谱系障碍 (NMOSD) 是一种中枢神经系统 (CNS) 的自身免疫性炎症性脱髓鞘疾病，伴有血脑屏障 (BBB) 破坏。小胶质细胞脂质代谢功能障碍被认为与 NMOSD 的神经病理学密切相关。然而，关于循环脂质在中枢神经系统脱髓鞘、细胞代谢和小胶质细胞功能中的功能相关性的证据有限。在这里，我们发现 NMOSD 患者血清低密度脂蛋白（LDL）与神经损伤标志物呈正相关。此外，我们在 NMOSD 小鼠模型中证明，LDL 通过渗漏 BBB 渗透中枢神经系统，直接激活小胶质细胞。这种激活导致髓磷脂碎片的过度吞噬、脂质代谢的抑制以及糖酵解的增加，最终加剧髓磷脂的损伤。我们还发现，旨在减少循环 LDL 的治疗干预措施可有效逆转小胶质细胞的脂质代谢功能障碍，并减轻 NMOSD 的脱髓鞘损伤。这些发现揭示了血清低密度脂蛋白与神经损伤之间正相关的分子和细胞机制，强调了降低循环脂质以减轻 NMOSD 急性脱髓鞘损伤的潜在治疗靶点。