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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of California System; University of California San Francisco; University of California System; University of California San Francisco; New York University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9358
• DOI: 10.1126/science.adk7844
• 发表日期: 2024-11-29
• 关键词: chromosome complement; myelin; mice; mortality; stroke

摘要

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.