Tlr7驱动年龄和阿尔茨海默病相关脱髓鞘的性别差异。

IF 45.8 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

摘要

阿尔茨海默病（AD）和其他与脱髓鞘相关的年龄相关疾病表现出性别差异。在这项工作中，我们使用单核转录组学来剖析性染色体和性腺在脱髓鞘和AD中的作用。在小鼠脱髓鞘模型中，我们确定了性染色体和性腺在髓鞘丢失前后改变小胶质细胞和少突胶质细胞反应中的作用。在表达APOE4的ad相关小鼠模型中，XY性染色体增强干扰素（IFN）应答和tau诱导的脱髓鞘。x连锁基因toll样受体7 （Tlr7）调节性别特异性IFN对髓磷脂的反应。Tlr7的缺失抑制了性别差异，同时防止脱髓鞘。在雄性小鼠中，给予TLR7抑制剂可以减轻tau诱导的运动损伤和脱髓鞘，这表明TLR7在男性偏倚的I型干扰素IFN反应中发挥作用，参与衰老和ad相关的脱髓鞘。

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

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Tlr7 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 (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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