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

• Published in: Science (American Association for the Advancement of Science) 2024-11, Vol.386 (6725), p.eadk7844
• Main Authors: Lopez-Lee, Chloe, Kodama, Lay, Fan, Li, Zhu, Daphne, Zhu, Jingjie, Wong, Man Ying, Ye, Pearly, Norman, Kendra, Foxe, Nessa R, Ijaz, Laraib, Yu, Fangmin, Chen, Hao, Carling, Gillian K, Torres, Eileen R, Kim, Rachel D, Dubal, Dena B, Liddelow, Shane A, Sinha, Subhash C, Luo, Wenjie, Gan, Li
• Format: Article
• Language: English
• Subjects: Age; Age Differences; Aging; Aging (artificial); Alleles; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Apolipoprotein E4; Apolipoprotein E4 - genetics; Chromosome deletion; Chromosomes; Demyelinating Diseases - genetics; Demyelinating Diseases - metabolism; Demyelination; Disease; Disease Models, Animal; Female; Females; Gender differences; Genes, X-Linked; Genotypes; Gonads; Hormones; Humans; Immune system; Interferon; Interferon Type I - metabolism; Male; Males; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; Myelin; Myelin Sheath - metabolism; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; NF-κB protein; Oligodendrocytes; Oligodendroglia - metabolism; Ovaries; Paralysis; Pathology; Phagocytosis; Proteins; Risk factors; Sex Characteristics; Sex chromosomes; Sex Chromosomes - genetics; Sex differences; Spatial analysis; Tau protein; tau Proteins - metabolism; Toll-Like Receptor 7 - antagonists & inhibitors; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; Toll-like receptors; Transcriptomics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adk7844

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 ( ), regulated sex-specific IFN response to myelin. Deletion of dampened sex differences while protecting against demyelination. Administering TLR7 inhibitor mitigated tau-induced motor impairment and demyelination in male mice, indicating that plays a role in the male-biased type I Interferon IFN response in aging- and AD-related demyelination.