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小胶质细胞通过中和氧化磷脂酰胆碱显著改善多发性硬化病变
作者:小柯机器人 发布时间:2021/2/19 15:58:59

加拿大卡尔加里大学V. Wee Yong团队的研究表明,多发性硬化病变中发现的氧化磷脂酰胆碱(OxPCs)介导神经退行性病变可被小胶质细胞中和。这一研究成果发表在2021年2月18日出版的国际学术期刊《自然-神经科学》上。

研究人员发现在多发性硬化症(MS)病变中发现的OxPCs是神经退行性病变的有效驱动因子,OxPCs之前被作为氧化应激最终产物的标记。培养的神经元和少突胶质细胞被OxPC杀死,而小胶质细胞则对此有所改善。注射OxPC后,小鼠脊髓出现局灶性脱髓鞘病变,并伴有明显的轴突丢失。OxPC病变中积累的小胶质细胞耗竭加剧了神经变性。

病变脊髓的单细胞RNA测序表明响应OxPC沉积的小鼠小胶质细胞产生TREM2high的独特子集。在人类MS病变中检测到TREM2,而TREM2-/-小鼠表现出恶化的OxPC病变。这些结果确定了OxPCs是有效的神经毒素,并表明通过TREM2增强小胶质细胞介导的OxPC清除可以帮助改善MS的神经变性。

研究人员表示,MS中发生的神经退行性病变导致残疾进展。因此,鉴定中和促进MS神经变性的机制至关重要。

附:英文原文

Title: Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia

Author: Yifei Dong, Charlotte DMello, William Pinsky, Brian M. Lozinski, Deepak K. Kaushik, Samira Ghorbani, Dorsa Moezzi, Dennis Brown, Francisca C. Melo, Stephanie Zandee, Tina Vo, Alexandre Prat, Shawn N. Whitehead, V. Wee Yong

Issue&Volume: 2021-02-18

Abstract: Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2high mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2/ mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS.

DOI: 10.1038/s41593-021-00801-z

Source: https://www.nature.com/articles/s41593-021-00801-z

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新IF:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex