White matter aging drives microglial diversity
Open accessAbstract
Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
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White-matter microglia reactivity has been related to aging and diseases.
“White-matter microglia reactivity has also been related to aging52 and diseases.53”
From Molecular and spatial signatures of mouse brain aging at single-cell resolution (2023) · cites this paper as [52]
Loss of myelin integrity is associated with secondary neuroinflammation.
“Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [3]
Myelin defects seem to be unique drivers of microglia activation in the ageing brain, challenging microglia with the uptake and digestion of large amounts of lipids and highly compacted membranes.
“By contrast, myelin defects seem to be unique drivers of microglia activation in the ageing brain (as previously shown3), which challenge microglia with the uptake and digestion of large amounts of lipids and highly compacted membranes.”
From Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease (2023) · cites this paper as [3]
Age decreases microglia-mediated clearance of myelin fragments, but white matter-restricted microglia are an age-dependent state able to clear age-associated damaged myelin.
“Age decreases microglia-mediated clearance of myelin fragments [329], but white matter-restricted microglia (WAM) are an age-dependent state able to clear age-associated damaged myelin [330].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [330]
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A carbon nanotube tape for serial-section electron microscopy of brain ultrastructure
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Dysregulation of brain and choroid plexus cell types in severe COVID-19
Yang, A. C., Kern, F., Losada, P. M., Agam, M. R., Maat, C. A., Schmartz, G. P., Fehlmann, T., Stein, J. A., Schaum, N., Lee, D. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03710-0 · Cited by 620 · see citing works
Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation
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Microglia regulate central nervous system myelin growth and integrity
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TREM2 drives microglia response to amyloid-β via SYK-dependent and -independent pathways
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Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
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Self-citationMolecular and spatial signatures of mouse brain aging at single-cell resolution
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“In a second and potentially related model, excessive myelin degradation can induce activation of phagocytosing microglia that become overloaded with myelin fragments.(52,55) In both scenarios, activated microglia can in turn activate astrocytes through secretion of pro-inflammatory cytokines and complement proteins.”
BackgroundThe neurobiology of long COVID
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Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice?
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Atlas of the aging mouse brain reveals white matter as vulnerable foci
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TREM2 dependent and independent functions of microglia in Alzheimer’s disease
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Microglia in multiple sclerosis: protectors turn destroyers
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Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration
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Acute ischemia induces spatially and transcriptionally distinct microglial subclusters
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White matter microglia heterogeneity in the CNS
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Characteristics of Neural Network Changes in Normal Aging and Early Dementia
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Microglia phagocytic mechanisms: Development informing disease
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TGF-β Signaling in Microglia: A Key Regulator of Development, Homeostasis and Reactivity
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Primary cilia-mediated regulation of microglial secretion in Alzheimer’s disease
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<scp>CNS</scp> macrophage contributions to myelin health
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Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
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Microglial states revisited: from homeostasis to disease
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TGFβ signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration
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ApoE expression across the CNS: Who, What, Where, When, and How (much)?
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- Authors
- Safaiyan, S., Besson-Girard, S., Kaya, T., Cantuti-Castelvetri, L., Liu, L., Ji, H., Schifferer, M., Gouna, G., Usifo, F., Kannaiyan, N., Fitzner, D., Xiang, X., Rossner, M. J., Brendel, M., Gokce, O., & Simons, M.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Göttingen (DE)
- Corresponding author
- Simons, Mikael
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 109
- Issue
- 7
- Pages
- 1100-1117.e10
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W3132186274
- Cited by
- 477
- References
- 82
- Citations by year
- 2026: 87 · 2025: 81 · 2024: 100 · 2023: 90 · 2022: 87 · 2021: 30 · 2012: 2
- FWCI
- 31.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Deutsche Forschungsgemeinschaft (EXC2145, ID390857198, TRR128-2, RO 4076/3-2, 390857198, RO5194/1-1, BR4580/1-1, TRR 274)
- National Alliance for Research on Schizophrenia and Depression
- European Research Council
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- white matter aging, disease-associated microglia, TREM2 signaling, apolipoprotein E, myelin degeneration, phagocytosis, lipid metabolism, microglial nodules, neurodegeneration
- MeSH terms
- Aging, Alzheimer Disease, Animals, Apolipoproteins E, Demyelinating Diseases, Gene Expression Regulation, Immunohistochemistry, Membrane Glycoproteins, Mice, Inbred C57BL, Myelin Sheath, Receptors, Immunologic, Signal Transduction, Sequence Analysis, RNA, Microglia, Mice, Knockout, Mice, Single-Cell Analysis, White Matter, Gray Matter
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.
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