p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice.

IF 14.7 1区 医学 Q1 NEUROSCIENCES
Sara I Graves, Charlton F Meyer, Karthik B Jeganathan, Darren J Baker
{"title":"p16-expressing microglia and endothelial cells promote tauopathy and neurovascular abnormalities in PS19 mice.","authors":"Sara I Graves, Charlton F Meyer, Karthik B Jeganathan, Darren J Baker","doi":"10.1016/j.neuron.2025.04.020","DOIUrl":null,"url":null,"abstract":"<p><p>Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPT<sup>P301S</sup>;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16<sup>Ink4a</sup> is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16<sup>Ink4a</sup>. Additionally, we found that PS19 mouse brains display p16<sup>Ink4</sup>-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16<sup>Ink4a</sup> deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16<sup>Ink4a</sup>-expressing endothelial cells and microglia.</p>","PeriodicalId":19313,"journal":{"name":"Neuron","volume":" ","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuron","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neuron.2025.04.020","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Cellular senescence is characterized by irreversible cell-cycle exit, a pro-inflammatory secretory phenotype, macromolecular damage, and deregulated metabolism. Senescent cells are highly associated with age-related diseases. We previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPTP301S;PS19) mutant mice. Here, we show that genetic ablation of the senescence mediator p16Ink4a is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes-including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment-were blunted in the absence of p16Ink4a. Additionally, we found that PS19 mouse brains display p16Ink4-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, we show that p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same phenotypes. Altogether, these results indicate that neurodegenerative disease in PS19 mice is driven, at least in part, by p16Ink4a-expressing endothelial cells and microglia.

表达p16的小胶质细胞和内皮细胞促进PS19小鼠的牛头病变和神经血管异常。
细胞衰老的特征是不可逆的细胞周期退出,促炎分泌表型,大分子损伤和代谢失调。衰老细胞与年龄相关疾病密切相关。我们之前证明了靶向消除衰老细胞可以预防tau (MAPTP301S;PS19)突变小鼠的神经退行性疾病。在这里,我们发现衰老介质p16Ink4a的基因消融足以减弱PS19小鼠的衰老特征。在缺乏p16Ink4a的情况下,疾病表型(包括神经炎症、磷酸化tau蛋白、神经变性和认知障碍)变得迟钝。此外,我们发现PS19小鼠大脑显示p16ink4依赖性神经血管改变,如血管扩张、血管密度增加、内皮细胞细胞外基质失调和星形细胞终足去极化。最后,我们发现内皮细胞和小胶质细胞中的p16Ink4a缺失会减弱许多相同的表型。总之,这些结果表明PS19小鼠的神经退行性疾病至少部分是由表达p16ink4a的内皮细胞和小胶质细胞驱动的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Neuron
Neuron 医学-神经科学
CiteScore
24.50
自引率
3.10%
发文量
382
审稿时长
1 months
期刊介绍: Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信