biostudies-literatureLopez-Lee CNEI NIH HHSNIA NIH HHSNIAMS NIH HHSeadk7844https://www.ebi.ac.uk/biostudies/studies/S-EPMC12396121biostudies-literatureUnknown386(6725)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 motoScience (New York, N.Y.)&lt;i&gt;Tlr7&lt;/i&gt; drives sex differences in age- and Alzheimer's disease-related demyelination.PMC12396121R01 AG068325R01 AG072758RF1 AG068325R01 AG064239RF1 AG079176R01 AG074541R01 AR074541R01 EY033353R01 AG054214Lopez-Lee CYu FFoxe NRLiddelow SAChen HCarling GKTorres ERZhu DDubal DBNorman KIjaz LZhu JSinha SCYe PKim RDGan LFan LLuo WKodama LWong MYfalse&lt;i&gt;Tlr7&lt;/i&gt; 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 moto2024-01-01T00:00:00Z2024 Nov2026-05-27T21:10:45.474Z2026-04-08T01:50:48.349ZS-EPMC123961213960792710.1126/science.adk7844