Tlr7 Drives Sex Differences in Age- and AD-related Demyelination [spatial transcriptomics]

Alzheimers disease (AD) and other age-related disorders associated with demyelination exhibit sex differences. Here, 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 role 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 response and tau-induced demyelination. The X-linked gene Toll-like receptor 7 (Tlr7) regulated sex-specific interferon 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 IFN-I response in aging- and AD-related demyelination. Spatial transcriptomic sequencing of mouse hemi brains investigating the effects of biological sex, sex hormones, and sex chromosomes on either cuprizone-induced demyelination or tau pathology阿尔茨海默病（Alzheimers disease, AD）及其他与脱髓鞘相关的年龄相关性疾病均存在性别差异。本研究利用单细胞核转录组学（single-nuclei transcriptomics）技术，解析了性染色体与性腺在脱髓鞘及阿尔茨海默病发生发展中的作用。在脱髓鞘小鼠模型中，我们明确了性染色体与性腺在髓鞘丢失前后调控小胶质细胞（microglia）与少突胶质细胞（oligodendrocyte）应答反应的功能。在表达APOE4的阿尔茨海默病相关小鼠模型中，携带XY性染色体的个体呈现增强的干扰素应答及tau蛋白诱导的脱髓鞘进程。X连锁基因Toll样受体7（Toll-like receptor 7, Tlr7）可调控髓鞘相关的性别特异性干扰素应答。敲除Tlr7可削弱性别差异，同时对脱髓鞘损伤起到保护作用。给雄性小鼠施用TLR7抑制剂可缓解tau蛋白诱导的运动功能障碍与脱髓鞘，这提示Tlr7在衰老及阿尔茨海默病相关脱髓鞘的雄性偏向性I型干扰素（IFN-I）应答中发挥关键调控作用。本研究还对小鼠半脑开展空间转录组测序，以探究生物性别、性激素及性染色体对铜嘧啶（cuprizone）诱导的脱髓鞘或tau蛋白病理的影响。