Ferroptosis of Microglia in Aging Human White Matter Injury

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY Annals of Neurology Pub Date : 2023-08-21 DOI:10.1002/ana.26770

Philip A. Adeniyi PhD, Xi Gong MD, Ellie MacGregor BS, Kiera Degener-O'Brien MD, Evelyn McClendon PhD, Mariel Garcia BA, Oscar Romero BA, Joshua Russell PhD, Taasin Srivastava PhD, Jeremy Miller PhD, C. Dirk Keene MD, PhD, Stephen A. Back MD, PhD

{"title":"Ferroptosis of Microglia in Aging Human White Matter Injury","authors":"Philip A. Adeniyi PhD, Xi Gong MD, Ellie MacGregor BS, Kiera Degener-O'Brien MD, Evelyn McClendon PhD, Mariel Garcia BA, Oscar Romero BA, Joshua Russell PhD, Taasin Srivastava PhD, Jeremy Miller PhD, C. Dirk Keene MD, PhD, Stephen A. Back MD, PhD","doi":"10.1002/ana.26770","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>We found that DM, which accumulated myelin debris were selectively enriched in the iron-binding protein light chain ferritin, and accumulated PLIN2-labeled lipid droplets. DM displayed lipid peroxidation injury and enhanced expression for TOM20, a mitochondrial translocase, and a sensor of oxidative stress. DM also displayed enhanced expression of the DNA fragmentation marker phospho-histone H2A.X. We identified a unique set of ferroptosis-related genes involving iron-mediated lipid dysmetabolism and oxidative stress that were preferentially expressed in WM injury relative to gray matter neurodegeneration.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>Ferroptosis appears to be a major mechanism of WM injury in Alzheimer's disease and vascular dementia. WM DM are a novel therapeutic target to potentially reduce the impact of WM injury and myelin loss on the progression of cognitive impairment. ANN NEUROL 2023;94:1048–1066</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"94 6","pages":"1048-1066"},"PeriodicalIF":8.1000,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26770","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.26770","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Objective

Because the role of white matter (WM) degenerating microglia (DM) in remyelination failure is unclear, we sought to define the core features of this novel population of aging human microglia.

Methods

We analyzed postmortem human brain tissue to define a population of DM in aging WM lesions. We used immunofluorescence staining and gene expression analysis to investigate molecular mechanisms related to the degeneration of DM.

Results

We found that DM, which accumulated myelin debris were selectively enriched in the iron-binding protein light chain ferritin, and accumulated PLIN2-labeled lipid droplets. DM displayed lipid peroxidation injury and enhanced expression for TOM20, a mitochondrial translocase, and a sensor of oxidative stress. DM also displayed enhanced expression of the DNA fragmentation marker phospho-histone H2A.X. We identified a unique set of ferroptosis-related genes involving iron-mediated lipid dysmetabolism and oxidative stress that were preferentially expressed in WM injury relative to gray matter neurodegeneration.

Interpretation

Ferroptosis appears to be a major mechanism of WM injury in Alzheimer's disease and vascular dementia. WM DM are a novel therapeutic target to potentially reduce the impact of WM injury and myelin loss on the progression of cognitive impairment. ANN NEUROL 2023;94:1048–1066

Abstract Image

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

老龄人白质损伤中的小胶质细胞下垂。

目的:由于白质(WM)退行性小胶质细胞(DM)在髓鞘再生失败中的作用尚不清楚，我们试图定义这种新型衰老人类小胶质细胞的核心特征。方法:我们分析了死后的人类脑组织，以确定衰老WM病变中DM的人群。我们通过免疫荧光染色和基因表达分析探讨了DM变性的分子机制。结果:我们发现，积累髓磷脂碎片的DM选择性地富集了铁结合蛋白轻链铁蛋白，并积累了plin2标记的脂滴。DM显示脂质过氧化损伤，线粒体转位酶TOM20表达增强，TOM20是氧化应激的传感器。DM也显示DNA片段标记磷酸化组蛋白H2A.X的表达增强。我们发现了一组独特的与铁中毒相关的基因，涉及铁介导的脂质代谢障碍和氧化应激，这些基因在与灰质神经变性相关的WM损伤中优先表达。解释:铁下垂似乎是阿尔茨海默病和血管性痴呆中WM损伤的主要机制。WM DM是一种新的治疗靶点，可以潜在地减少WM损伤和髓磷脂损失对认知功能障碍进展的影响。神经科学学报[j]; 2009; 44(4):1048-1066。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.