Microglial brain region-dependent diversity and selective regional sensitivities to aging
Open accessAbstract
Microglia have critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific, spatially restricted patterns, the origins of which are unknown. We performed to our knowledge the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse, and found that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune-vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during aging. Microglial diversity may enable regionally localized homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.
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Presence of a type I IFN signature in brain cells, in particular microglia, is increasingly associated with ageing and neurodegenerative disease in various species.
“The presence of a type I IFN signature in brain cells, in particular in microglia, is increasingly being associated with ageing and neurodegenerative disease in various species13,15,39,44–50.”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [48]
The Results section, “Pathways underpinning region-specific microglial ageing profiles” (page unavailable), reports that interferon-pathway genes increased with age, predominantly in cerebellar microglia. Another Results passage identifies the type I interferon receptor as a predicted upstream regulator. The paper does not establish an interferon signature associated with neurodegenerative disease across various species. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHeterogeneity of microglia between different brain areas and between different sexes is increasingly recognized.
“Heterogeneity of microglia between different brain areas (Grabert et al., 2016) and between different sexes (Villa et al., 2018) is increasingly recognized.”
From The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques (2019) · cites this paper as Grabert et al., 2016
Microglia also show alterations in gene expression in the aging brain, and these changes vary by brain region, with cerebellar microglia showing the most changes with age, the same result found for astrocytes.
“Microglia also show alterations in gene expression in the aging brain, and, as with astrocytes, these changes vary by brain region, with cerebellar microglia showing the most changes with age, the same result we found for astrocytes (Grabert et al., 2016).”
From The aging astrocyte transcriptome from multiple regions of the mouse brain. (2018) · cites this paper as Grabert et al., 2016
Transcriptional analysis of microglia from different regions of the healthy adult brain revealed remarkable regional diversity beyond a core transcriptome.
“Recent transcriptional analysis of microglia from different regions of the healthy adult brain has revealed remarkable regional diversity of microglia beyond a core transcriptome (45).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [45]
There was surprisingly limited overlap in microglial genes regulated by aging in human versus mouse.
“There was surprisingly limited overlap, however, in microglial genes regulated by aging in human versus mouse (Grabert et al., 2016; Galatro et al., 2017)”
From Microglia in Alzheimer’s disease (2018) · cites this paper as Grabert et al., 2016
Mouse microglia show region-specific transcriptional profiles and age-dependent regional variability, and cerebellar and hippocampal microglia exist in a more immune-vigilant state than forebrain microglia.
“a genome-wide analysis of gene expression in microglia from different brain regions across the adult lifespan of the mouse was performed found that there are region-specific transcriptional profiles and age-dependent regional variability in gene expression59.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [59]
Microglia display transcriptional heterogeneity that depends on age and on brain region.
“This study describes the age-dependent and region-dependent transcriptional heterogeneity of microglia.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [59]
Other genes previously attributed to microglial regional heterogeneity may reflect differential abundance of non-microglial populations in CD11b-selected bulk samples.
“Meanwhile, other genes previously attributed to microglial regional heterogeneity could be due to differential abundance of non-microglial populations in bulk samples with the CD11b selection (Grabert et al., 2016).”
From Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing (2019) · cites this paper as Grabert et al., 2016
Acutely isolated cerebellar microglia are significantly more efficient in uptake of apoptotic cells or other biological materials.
“In parallel, we and others found that acutely isolated cbMg are significantly more efficient in the uptake of apoptotic cells or other biological materials41.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [41]
This morphological variety suggests that microglia respond to different cortical layers or brain regions and may reflect microglial subtypes in the brain.
“This morphological diversity is indicative of microglia responding to distinct cortical layers/brain-regions and potentially reflect microglia subtypes found within the brain”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Grabert et al., 2016
Microglial gene expression changes with aging.
“and that microglial gene expression changes with aging (110–112).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [111]
In the same study, the hippocampal microglia showed a 30% decline in overall gene expression between the ages 4 and 22 months.
“In the same study, the hippocampal microglia showed a 30% decline in overall gene expression between the ages 4 and 22 months, a finding the authors referred to as 'potential disengagement of aged hippocampal microglia with their environment compared to their young adult counterparts' (Grabert and Michoel, 2016).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Grabert and Michoel, 2016
The only report examining the brain-region-specific transcriptional profile of microglia demonstrated a heightened baseline expression of genes associated with metabolism and immune response in the cerebellum and hippocampus.
“The only report examining the brain-region-specific transcriptional profile of microglia demonstrated a heightened baseline expression of genes associated with metabolism and immune response in the cerebellum and hippocampus (Grabert and Michoel, 2016).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Grabert and Michoel, 2016
There was an age-dependent increase in the expression of amplifying receptors (such as TREM1, SIRPB1a, etc), and a corresponding reduction (eg, CD200 receptor) or stable expression (eg, CD300a) of inhibitory receptors in microglia.
“For example, there was an age-dependent increase in the expression of amplifying receptors (such as, TREM1, SIRPB1a, etc), and a corresponding reduction (eg, CD200 receptor) or stable expression (eg, CD300a) of inhibitory receptors in microglia.”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Grabert and Michoel, 2016
Aging induced an overall increase in the expression of immunoreceptor tyrosine-based activation motif (ITAM) with no change in immunoreceptor tyrosine-based inhibitory motif.
“Notably, aging induced an overall increase in the expression of immunoreceptor tyrosine-based activation motif (ITAM) with no change in immunoreceptor tyrosine-based inhibitory motif.”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Grabert and Michoel, 2016
An extensive overlap was observed between human microglia and three independent mouse microglial gene expression data sets; median Δ percentiles were 14.3, 20.4 and 9.3.
“An extensive overlap was observed between human and these three independent mouse microglial gene expression data sets ( Fig. 2c ). The median ∆ percentiles were 14.3, 20.4 and 9.3 for our own expression data set, that of Grabert et al. 23 and that of Matcovich-Natan et al. 24 , respectively.”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [23]
To minimize the reported effect of brain region on microglial gene expression, only cortical microglia were included in comparisons.
“To minimize the reported effect of brain region on microglial gene expression 6,23,24 , only cortical microglia were included in our comparisons.”
From Transcriptomic analysis of purified human cortical microglia reveals age-associated changes (2017) · cites this paper as [23]
Microglia are highly dynamic cells strongly influenced by environmental signals, resulting in distinct phenotypes and functions across brain regions.
“Microglia are highly dynamic cells that are strongly influenced by different environmental signals which result in distinct phenotypes and functions across brain regions4–9.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [6]
Regional and age-related differences in microglial density, morphology, gene, and protein expression have previously been described for both animals and humans.
“Regional and age-related differences in microglial density, morphology, gene, and protein expression have previously been described for both animals and humans5,6,9,60,61.”
From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [6]
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Microglia Function in the Central Nervous System During Health and Neurodegeneration
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InfluentialYoung bone marrow transplantation preserves learning and memory in old mice
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- Authors
- Grabert, K., Michoel, T., Karavolos, M. H., Clohisey, S., Baillie, J. K., Stevens, M. P., Freeman, T. C., Summers, K. M., & McColl, B. W.
- Affiliations
- Roslin Institute (GB)
- Corresponding author
- McColl, Barry W
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2016-01-18
- Volume
- 19
- Issue
- 3
- Pages
- 504-516
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4768346
- OpenAlex
- W2261364877
- Cited by
- 1,151
- References
- 55
- Citations by year
- 2026: 84 · 2025: 82 · 2024: 99 · 2023: 108 · 2022: 139 · 2021: 139 · 2020: 122 · 2019: 142 · 2018: 102 · 2017: 88 · 2016: 44
- FWCI
- 68.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (103258/Z/13/Z)
- University of Edinburgh
- Darwin Trust of Edinburgh
- Medical Research Council (MR/L003384/1, MR/K001744/1)
- Biotechnology and Biological Sciences Research Council (BBS/E/D/05191131, BBS/E/D/20251969, BBS/E/D/20211552, BBS/E/D/20241864, BBS/E/D/20211551, BBS/E/D/20241863, BB/ J004243/1, BB/I001107/1, BB /J004332/1, BBS/E/D/20310000)
- Natural Environment Research Council (NBAF010003, R8/H10/56)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, regional heterogeneity, brain aging, age-related neurodegeneration, cerebellum, hippocampus, bioenergetics, immune regulation, neuroinflammation, mouse brain
- MeSH terms
- Aging, Animals, Brain, Phenotype, Microglia, Mice, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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