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Cited by 49Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesAlzheimer's disease research and treatments

Tlr7 drives sex differences in age- and Alzheimer’s disease–related demyelination

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Lopez-Lee, Chloe, Kodama, Lay, Fan, Li, Zhu, Daphne, Zhu, Jingjie, Wong, Man Ying, Ye, Pearly, Norman, Kendra +12 more·2024·Science
DOI 10.1126/science.adk7844PMC PMC12396121
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Abstract

Alzheimer’s disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. In this work, we used single-nuclei transcriptomics to dissect the contributions of sex chromosomes and gonads in demyelination and AD. In a mouse model of demyelination, we identified the roles of sex chromosomes and gonads in modifying microglia and oligodendrocyte responses before and after myelin loss. In an AD-related mouse model expressing APOE4, XY sex chromosomes heightened interferon (IFN) response and tau-induced demyelination. The X-linked gene, Toll-like receptor 7 ( Tlr7 ), regulated sex-specific IFN response to myelin. Deletion of Tlr7 dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that Tlr7 plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.

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Authors
Lopez-Lee, C., Kodama, L., Fan, L., Zhu, D., Zhu, J., Wong, M. Y., Ye, P., Norman, K., Foxe, N. R., Ijaz, L., Yu, F., Chen, H., Carling, G. K., Torres, E. R., Kim, R. D., Dubal, D. B., Liddelow, S. A., Sinha, S. C., Luo, W., & Gan, L.
Affiliations
  • Weill Cornell Medicine (US)
  • University of California, San Francisco (US)
  • New York University (US)
  • NYU Langone Health (US)
Corresponding author
Gan, Li
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-11-29
Volume
386
Issue
6725
Pages
eadk7844-eadk7844
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.adk7844
PMC
PMC12396121
OpenAlex
W4404809446
Cited by
49
References
73
Citations by year
2026: 25 · 2025: 23 · 2024: 1
FWCI
7.64
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Alzheimer's Association
  • Cure Alzheimer's Fund
  • University of Virginia
  • National Institutes of Health
  • National Institute on Aging (RF1AG079176, R01AG064239, RF1AG068325, R01AG054214, R01AG068325, R01AG079176, R01AG072758, R01AG074541)
  • National Eye Institute (R01EY033353)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR074541)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, demyelination, sex differences, TLR7, type I interferon response, sex chromosomes, gonads, microglia, oligodendrocytes, APOE ε4, tau protein, aging, motor impairment
MeSH terms
Aging, Alzheimer Disease, Animals, Demyelinating Diseases, Disease Models, Animal, Female, Humans, Interferon Type I, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Myelin Sheath, Oligodendroglia, Sex Characteristics, Sex Chromosomes, tau Proteins, Microglia, Genes, X-Linked, Toll-Like Receptor 7, Mice, Apolipoprotein E4

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