Cited by 477Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesSingle-cell and spatial transcriptomics

White matter aging drives microglial diversity

Open access
Safaiyan, Shima, Besson-Girard, Simon, Kaya, Tuğberk, Cantuti-Castelvetri, Ludovico, Liu, Lu, Ji, Hao, Schifferer, Martina, Gouna, Garyfallia +8 more·2021·Neuron

Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2021.01.027

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • White-matter microglia reactivity has been related to aging and diseases.

    “White-matter microglia reactivity has also been related to aging52 and diseases.53”
  • 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.”
  • 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.”
  • 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]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
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
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.

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 ›

Are you an author, or do you see a problem with this page? Request a review