<i>Tlr7</i> drives sex differences in age- and Alzheimer’s disease–related demyelination
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 (<i>Tlr7</i>), regulated sex-specific IFN response to myelin. Deletion of <i>Tlr7</i> dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that <i>Tlr7</i> plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.
Authors
- Subhash C. Sinha (ORCID: https://orcid.org/0000-0001-8916-5677)
- Man Ying Wong (ORCID: https://orcid.org/0000-0002-2165-9328)
- Pearly Ye
- Dena B. Dubal (ORCID: https://orcid.org/0000-0001-7504-4372)
- Fangmin Yu
- Daphne Zhu
- Chloe Lopez-Lee (ORCID: https://orcid.org/0000-0002-1013-3005)
- Laraib Ijaz
- Lay Kodama (ORCID: https://orcid.org/0000-0001-8419-8445)
- Eileen Ruth S. Torres (ORCID: https://orcid.org/0000-0002-5340-8734)
- Gillian Carling (ORCID: https://orcid.org/0000-0002-1504-1716)
- Rachel D. Kim (ORCID: https://orcid.org/0000-0001-6361-6206)
- Wenjie Luo (ORCID: https://orcid.org/0000-0003-3752-8266)
- Li Gan (ORCID: https://orcid.org/0000-0003-4600-275X)
- Shane A. Liddelow (ORCID: https://orcid.org/0000-0002-0840-1437)
- Li Fan (ORCID: https://orcid.org/0000-0003-1780-6919)
- Nessa Foxe
- Hao Chen (ORCID: https://orcid.org/0000-0002-9179-5720)
- Kendra Norman
- Jingjie Zhu (ORCID: https://orcid.org/0000-0001-8169-4873)
Institutions
- University of California, San Francisco (US)
- Cornell University (US)
- Weill Cornell Medicine (US)
- New York University (US)
Publication Details
- Journal
- Science
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1126/science.adk7844
- Citations
- 32
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 7.92
Funders
- Alzheimer's Association
- Cure Alzheimer's Fund
- University of Virginia
- National Institutes of Health
- National Eye Institute