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

被引：12

作者：

Lopez-Lee, Chloe ^{[1
,2
]}

Kodama, Lay ^{[1
,3
]}

Fan, Li ^{[1
]}

Zhu, Daphne ^{[1
]}

Zhu, Jingjie ^{[1
]}

Wong, Man Ying ^{[1
]}

Ye, Pearly ^{[1
]}

Norman, Kendra ^{[1
]}

Foxe, Nessa R. ^{[1
]}

Ijaz, Laraib ^{[1
]}

Yu, Fangmin ^{[1
]}

Chen, Hao ^{[1
]}

Carling, Gillian K. ^{[1
,2
]}

Torres, Eileen R. ^{[1
]}

Kim, Rachel D. ^{[4
]}

Dubal, Dena B. ^{[5
]}

Liddelow, Shane A. ^{[4
,6
,7
,8
]}

Sinha, Subhash C. ^{[1
]}

Luo, Wenjie ^{[1
]}

Gan, Li ^{[1
,2
]}

机构：

[1] Weill Cornell Med, Helen & Robert Appel Inst Alzheimers Dis Res, Brain & Mind Res Inst, New York, NY 10065 USA

[2] Weill Cornell Med, Neurosci Grad Program, New York, NY 10065 USA

[3] Univ Calif San Francisco, Neurosci Grad Program, San Francisco, CA USA

[4] NYU Grossman Sch Med, Neurosci Inst, New York, NY USA

[5] Univ Calif San Francisco, Weill Inst Neurosci, Dept Neurol, San Francisco, CA USA

[6] NYU Grossman Sch Med, Dept Neurosci & Physiol, New York, NY USA

[7] NYU, Grossman Sch Med, Dept Pathol, New York, NY USA

[8] NYU Grossman Sch Med, Parekh Ctr Interdisciplinary Neurol, New York, NY USA

来源：

SCIENCE | 2024年 / 386卷 / 6725期

关键词：

CHROMOSOME COMPLEMENT; MYELIN; MICE; MORTALITY; STROKE;

D O I：

10.1126/science.adk7844

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

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