Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Ryan K. Shahidehpour; Rebecca E. Higdon; Nicole G. Crawford; Janna H. Neltner; Eseosa T. Ighodaro; Ela Patel; Douglas Price; Peter T. Nelson; Adam D. Bachstetter

doi:10.1016/j.neurobiolaging.2020.12.003

Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Ryan K. Shahidehpour, Rebecca E. Higdon, Nicole G. Crawford, Janna H. Neltner, Eseosa T. Ighodaro, Ela Patel, Douglas Price, Peter T. Nelson, Adam D. Bachstetter

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

137 Scopus citations

Abstract

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were done for total microglia, two microglia morphologies (hypertrophic, and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared to controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy (LATE). These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.

Original language	English
Pages (from-to)	19-27
Number of pages	9
Journal	Neurobiology of Aging
Volume	99
DOIs	https://doi.org/10.1016/j.neurobiolaging.2020.12.003
State	Published - Mar 2021

Bibliographical note

Publisher Copyright:
© 2020 The Author(s)

Funding

We are profoundly grateful to all study participants who make this research possible. Research reported in this publication was supported by the National Institutes of Health under award numbers P30 AG028383, R35 GM124977, and R21AG066865. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. The corresponding author, Adam Bachstetter, PhD, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Graphical abstract was created with BioRender.com. Financial support: Research reported in this publication was supported by the National Institutes of Health under award numbers P30 AG028383 , R35 GM124977 , and R21AG066865 .

Funders	Funder number
National Institutes of Health (NIH)	P30 AG028383, R21AG066865
National Institutes of Health (NIH)
National Institute of General Medical Sciences	R35GM124977
National Institute of General Medical Sciences

Keywords

Aging
microglia morphology
neurodegeneration
neuroinflammation
neuropathology
senescence

ASJC Scopus subject areas

General Neuroscience
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neurobiolaging.2020.12.003

Cite this

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title = "Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain",

abstract = "Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were done for total microglia, two microglia morphologies (hypertrophic, and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared to controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy (LATE). These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.",

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note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

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doi = "10.1016/j.neurobiolaging.2020.12.003",

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AU - Higdon, Rebecca E.

AU - Crawford, Nicole G.

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AU - Ighodaro, Eseosa T.

AU - Patel, Ela

AU - Price, Douglas

AU - Nelson, Peter T.

AU - Bachstetter, Adam D.

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N2 - Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were done for total microglia, two microglia morphologies (hypertrophic, and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared to controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy (LATE). These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.

AB - Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were done for total microglia, two microglia morphologies (hypertrophic, and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared to controls, the number of dystrophic microglia was greater in cases with either Alzheimer's disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy (LATE). These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.

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KW - neuropathology

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Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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