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

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2024-11-29 DOI:10.1126/science.adk7844

Chloe Lopez-Lee, Lay Kodama, Li Fan, Daphne Zhu, Jingjie Zhu, Man Ying Wong, Pearly Ye, Kendra Norman, Nessa R Foxe, Laraib Ijaz, Fangmin Yu, Hao Chen, Gillian K Carling, Eileen R Torres, Rachel D Kim, Dena B Dubal, Shane A Liddelow, Subhash C Sinha, Wenjie Luo, Li Gan

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引用次数: 0

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.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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