小胶质细胞中的自噬相关蛋白5（Atg5）调节阿尔茨海默病中对产后神经发生的性别特异性影响。

Atg5 in microglia regulates sex-specific effects on postnatal neurogenesis in Alzheimer's disease.

作者信息

Walter Ellen, Angst Gabrielle, Bollinger Justin, Truong Linh, Ware Elena, Wohleb Eric S, Fan Yanbo, Wang Chenran

机构信息

Department of Cancer Biology, University of Cincinnati College Medicine, Cincinnati, OH, USA.

Department of Radiation Oncology, Ohio State Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and College of Medicine at The Ohio State University, Columbus, OH, USA.

出版信息

NPJ Aging. 2025 Mar 16;11(1):18. doi: 10.1038/s41514-025-00209-0.

DOI:10.1038/s41514-025-00209-0

PMID:40091054

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11911432/

Abstract

Female Alzheimer's disease (AD) patients display greater cognitive deficits and worse AD pathology as compared to male AD patients. In this study, we found that conditional knockout (cKO) of Atg5 in female microglia failed to obtain disease-associated microglia (DAM) gene signatures in familiar AD mouse model (5xFAD). Next, we analyzed the maintenance and neurogenesis of neural stem cells (NSCs) in the hippocampus and subventricular zone (SVZ) from 5xFAD mice with Atg5 cKO. Our data indicated that Atg5 cKO reduced the NSC number in hippocampus of female but not male 5xFAD mice. However, in the SVZ, Atg5 cKO only impaired NSCs in male 5xFAD mice. Interestingly, female 5xFAD;Fip200 cKO mice and 5xFAD;Atg14 cKO mice did not show NSC defects. These autophagy genes cKO 5xFAD mice exhibited a higher neurogenesis activity in their SVZ. Together, our data indicate a sex-specific role for microglial Atg5 in postnatal neurogenesis in AD mice.

摘要

与男性阿尔茨海默病（AD）患者相比，女性AD患者表现出更严重的认知缺陷和更糟糕的AD病理特征。在本研究中，我们发现在常见的AD小鼠模型（5xFAD）中，雌性小胶质细胞中Atg5的条件性敲除（cKO）未能获得与疾病相关的小胶质细胞（DAM）基因特征。接下来，我们分析了Atg5 cKO的5xFAD小鼠海马体和脑室下区（SVZ）中神经干细胞（NSC）的维持和神经发生情况。我们的数据表明，Atg5 cKO减少了雌性而非雄性5xFAD小鼠海马体中的NSC数量。然而，在SVZ中，Atg5 cKO仅损害了雄性5xFAD小鼠的NSC。有趣的是，雌性5xFAD;Fip200 cKO小鼠和5xFAD;Atg14 cKO小鼠未表现出NSC缺陷。这些自噬基因cKO的5xFAD小鼠在其SVZ中表现出更高的神经发生活性。总之，我们的数据表明小胶质细胞Atg5在AD小鼠出生后神经发生中具有性别特异性作用。