据介绍，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。
研究人员使用单核转录组学来分析性染色体和性腺，在脱髓鞘和阿尔茨海默病中的作用。在脱髓鞘的小鼠模型中，研究人员确定了性染色体和生殖腺在髓鞘缺失前后，修饰小胶质细胞和少突胶质细胞反应中的角色。
在表达APOE4的AD相关小鼠模型中，XY性染色体增强了干扰素（IFN）反应和tau诱导的脱髓鞘。X连锁基因Toll样受体7（Tlr7）调节对髓磷脂的性别特异性IFN反应。
Tlr7的缺失抑制了性别差异，同时防止了脱髓鞘。TLR7抑制剂减轻了雄性小鼠tau诱导的运动损伤和脱髓鞘，表明TLR7在衰老和AD相关脱髓鞘中的，雄性偏倚I型干扰素-IFN反应中起作用。
附：英文原文
Title: Tlr7 drives sex differences in age- and Alzheimer’s disease–related demyelination
Author: 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
Issue&Volume: 2024-11-29
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.
DOI: adk7844
Source: https://www.science.org/doi/10.1126/science.adk7844