Ferroptosis of Microglia in Aging Human White Matter Injury

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

doi:10.1002/ana.26770

Ferroptosis of Microglia in Aging Human White Matter Injury

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

Pediatrics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1048-1066
Number of pages	19
Journal	Annals of Neurology
Volume	94
Issue number	6
DOIs	https://doi.org/10.1002/ana.26770
State	Published - Dec 2023

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1002/ana.26770

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title = "Ferroptosis of Microglia in Aging Human White Matter Injury",

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.",

author = "Adeniyi, {Philip A.} and Xi Gong and Ellie MacGregor and Kiera Degener-O'Brien and Evelyn McClendon and Mariel Garcia and Oscar Romero and Joshua Russell and Taasin Srivastava and Jeremy Miller and Keene, {C. Dirk} and Back, {Stephen A.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2023",

month = dec,

doi = "10.1002/ana.26770",

language = "English (US)",

volume = "94",

pages = "1048--1066",

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T1 - Ferroptosis of Microglia in Aging Human White Matter Injury

AU - Adeniyi, Philip A.

AU - Gong, Xi

AU - MacGregor, Ellie

AU - Degener-O'Brien, Kiera

AU - McClendon, Evelyn

AU - Garcia, Mariel

AU - Romero, Oscar

AU - Russell, Joshua

AU - Srivastava, Taasin

AU - Miller, Jeremy

AU - Keene, C. Dirk

AU - Back, Stephen A.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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Ferroptosis of Microglia in Aging Human White Matter Injury

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