<i>Tlr7</i> drives sex differences in age- and Alzheimer’s disease–related demyelination
Chloe Lopez-Lee, Lay Kodama, Li Fan, Daphne Zhu, Jingjie Zhu, Man Ying Wong, Pearly Ye, Kendra Norman, Nessa Foxe, Laraib Ijaz, Fangmin Yu, Hao Chen, Gillian Carling, Eileen Ruth S. Torres, Rachel D. Kim, Dena B. Dubal, Shane A. Liddelow, Subhash C. Sinha, Wenjie Luo, Li Gan
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.