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Cited by 23Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeurogenesis and neuroplasticity mechanisms

Trem2-deficiency aggravates and accelerates age-related myelin degeneration

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McCray, Tyler J., Bedford, Logan M., Bissel, Stephanie J., Lamb, Bruce T.·2024·Acta Neuropathologica Communications
DOI 10.1186/s40478-024-01855-3PMC PMC11411802
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Abstract

Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.

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Authors
McCray, T. J., Bedford, L. M., Bissel, S. J., & Lamb, B. T.
Affiliations
  • Indiana University School of Medicine (US)
  • Indiana University Indianapolis (US)
Corresponding author
Lamb, Bruce T.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2024-09-19
Volume
12
Issue
1
Pages
154-154
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-024-01855-3
PMC
PMC11411802
OpenAlex
W4402656481
Cited by
23
References
25
Citations by year
2026: 16 · 2025: 7
FWCI
3.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (U54 AG054345, RF1 AG074566, RF1 AG051495, F31 AG074628)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
TREM2, TREM2 deficiency, microglia, remyelination, demyelination, striatum, oligodendrocyte precursor cells, myelin phagocytosis, endoplasmic reticulum stress response, neurodegeneration, aging
MeSH terms
Remyelination, Aging, Animals, Demyelinating Diseases, Female, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Myelin Sheath, Phagocytosis, Receptors, Immunologic, Microglia, Mice, Knockout, Mice, Endoplasmic Reticulum Stress

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