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Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain
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Abstract
Abstract Microglia activation—typically described in terms of hypertrophic appearance—is a well-established feature of aging. Recent studies have suggested that microglia dystrophy, not activation, may increase the propagation of progressive neurodegenerative diseases such as Alzheimer’s disease (AD). Yet, a clear understanding of cause and consequences of dystrophic microglia is lacking. Although frequently observed in diseased brains, the appearance of dystrophic microglia in the hippocampus of individuals free of cognitive impairment suggests that microglia may be undergoing senescence with age, leading to dystrophy. Therefore, we hypothesized that chronological age could be a significant contributor to the presence of dystrophic microglia. To investigate this relationship, we employed stereological counts of total microglia, hypertrophic, and dystrophic microglia across the decades of the human lifespan. The microglia counts were performed in the frontal cortex gray and white matter and the CA1 subregion of the hippocampus in individuals without known neurodegenerative disease. There was age-associated increase in the number of dystrophic microglia in the CA1 region and the frontal cortex gray matter related to age. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia, suggesting that aging alone was not sufficient to explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia phenotype. Compared to controls without neuropathology, the number of dystrophic microglia was significantly greater in aged-matched cases with either AD, dementia with Lewy bodies, or LATE-NC. These results provide evidence that healthy aging is only associated with a modest increase in dystrophic microglia and suggest that dystrophic microglia may be a disease-associated microglia phenotype. Finally, we found strong evidence for iron homeostasis changes, with increases in ferritin light chain, in dystrophic microglia compared to ramified or hypertrophic microglia. Based on our findings, microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Future work is required to understand the links between the increase in dystrophic microglia and neurodegenerative disorders.
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“Moreover, the AD-associated microglia response in the hippocampus has been proposed to be linked to tau pathology (Shahidehpour et al., 2021; Streit et al., 2020; Navarro et al., 2018).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Shahidehpour et al., 2021
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“One study by Shahidehpour et al. suggests that there is increased ferritin accumulation in human microglia in ND but not old age, and proposed altered iron homeostasis as a distinguishing factor between aged ‘healthy’ microglia and those associated with neurodegeneration [132].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [132]
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Metadata
- Authors
- Shahidehpour, R. K., Higdon, R. E., Crawford, N. G., Neltner, J. H., Ighodaro, E. T., Patel, E., Price, D., Nelson, P. T., & Bachstetter, A. D.
- Affiliations
- University of Kentucky (US)
- University of Kentucky HealthCare (US)
- Corresponding author
- Bachstetter, Adam D.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 99
- Pages
- 19-27
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC8293930
- OpenAlex
- W3120102977
- Cited by
- 173
- References
- 35
- Citations by year
- 2026: 16 · 2025: 31 · 2024: 27 · 2023: 35 · 2022: 39 · 2021: 25
- FWCI
- 12.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of General Medical Sciences (R35 GM124977)
- National Institutes of Health
- National Institute on Aging (P30 AG028383, R21AG066865)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- microglial morphology, neurodegenerative diseases, healthy aging, cellular senescence, Alzheimer's disease, dementia with Lewy bodies, limbic-predominant age-related TDP-43 encephalopathy, iron homeostasis, hippocampus, frontal cortex, human brain
- MeSH terms
- Healthy Aging, Female, Frontal Lobe, Hippocampus, Homeostasis, Humans, Hypertrophy, Iron, Male, Cellular Senescence, Microglia, Neurodegenerative Diseases
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