| Title | Tlr7 drives sex differences in age- and Alzheimer's disease-related demyelination. |
| Publication Type | Journal Article |
| Year of Publication | 2024 |
| Authors | Lopez-Lee C, Kodama L, Fan L, Zhu D, Zhu J, Wong MYing, Ye P, Norman K, Foxe NR, Ijaz L, Yu F, Chen H, Carling GK, Torres ER, Kim RD, Dubal DB, Liddelow SA, Sinha SC, Luo W, Gan L |
| Journal | Science |
| Volume | 386 |
| Issue | 6725 |
| Pagination | eadk7844 |
| Date Published | 2024 Nov 29 |
| ISSN | 1095-9203 |
| Keywords | Aging, Alzheimer Disease, Animals, Apolipoprotein E4, Demyelinating Diseases, Disease Models, Animal, Female, Genes, X-Linked, Humans, Interferon Type I, Male, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Microglia, Myelin Sheath, Oligodendroglia, Sex Characteristics, Sex Chromosomes, tau Proteins, Toll-Like Receptor 7 |
| 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. |
| DOI | 10.1126/science.adk7844 |
| Alternate Journal | Science |
| PubMed ID | 39607927 |