Department of Neurology, China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Sci Transl Med. 2024 Feb 28;16(736):eadg5116. doi: 10.1126/scitranslmed.adg5116.
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.
视神经脊髓炎谱系疾病（NMOSD）是一种中枢神经系统自身免疫性星形胶质病，由水通道蛋白 4（AQP4）抗体介导，导致星形胶质细胞损伤，随后脱髓鞘和轴突损伤。通过星形胶质细胞衍生的细胞外囊泡（ADEVs）进行细胞外通讯，与星形胶质细胞病变的相关性受到越来越多的关注。然而，ADEVs 在多大程度上促进 NMOSD 的发病机制尚不清楚。在这里，通过对患者衍生的 ADEVs 进行蛋白质组学筛选，我们观察到 AQP4-Abs 阳性 NMOSD 患者中富含载脂蛋白 E（APOE）的 ADEVs 增加。在 NMOSD 小鼠模型中，APOE 模拟肽 APOE 的脑内注射可减轻小胶质细胞反应、神经炎症和脑损伤。APOE 在 NMOSD 发病机制中的保护作用进一步通过 APOE 缺陷型小鼠的病变体积加剧得到证实，而外源性 APOE 给药可挽救这一结果。APOE 受体脂蛋白受体相关蛋白 1（LRP1）的基因敲低可阻断 APOE 给药的修复作用。来自 NMOSD 患者和健康对照者的转输 ADEVs 也可减轻 NMOSD 小鼠的星形胶质细胞丢失、反应性小胶质细胞增生和脱髓鞘。与健康对照者相比，NMOSD 患者衍生的 ADEVs 具有稍大的有益效果，在 APOE 小鼠中进一步增强。这些结果表明，星形胶质细胞衍生的细胞外囊泡中的 APOE 可能介导 NMOSD 中具有疾病修饰作用的星形胶质细胞-小胶质细胞交叉对话。
