在tau转基因小鼠模型中,FKBP52过表达加速海马依赖性记忆损伤。

IF 5.4 Q1 GERIATRICS & GERONTOLOGY
Marangelie Criado-Marrero, Niat T Gebru, Lauren A Gould, Danielle M Blazier, Yamile Vidal-Aguiar, Taylor M Smith, Salma S Abdelmaboud, Lindsey B Shelton, Xinming Wang, Jan Dahrendorff, David Beaulieu-Abdelahad, Chad A Dickey, Laura J Blair
{"title":"在tau转基因小鼠模型中,FKBP52过表达加速海马依赖性记忆损伤。","authors":"Marangelie Criado-Marrero,&nbsp;Niat T Gebru,&nbsp;Lauren A Gould,&nbsp;Danielle M Blazier,&nbsp;Yamile Vidal-Aguiar,&nbsp;Taylor M Smith,&nbsp;Salma S Abdelmaboud,&nbsp;Lindsey B Shelton,&nbsp;Xinming Wang,&nbsp;Jan Dahrendorff,&nbsp;David Beaulieu-Abdelahad,&nbsp;Chad A Dickey,&nbsp;Laura J Blair","doi":"10.1038/s41514-021-00062-x","DOIUrl":null,"url":null,"abstract":"<p><p>Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-021-00062-x","citationCount":"9","resultStr":"{\"title\":\"FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.\",\"authors\":\"Marangelie Criado-Marrero,&nbsp;Niat T Gebru,&nbsp;Lauren A Gould,&nbsp;Danielle M Blazier,&nbsp;Yamile Vidal-Aguiar,&nbsp;Taylor M Smith,&nbsp;Salma S Abdelmaboud,&nbsp;Lindsey B Shelton,&nbsp;Xinming Wang,&nbsp;Jan Dahrendorff,&nbsp;David Beaulieu-Abdelahad,&nbsp;Chad A Dickey,&nbsp;Laura J Blair\",\"doi\":\"10.1038/s41514-021-00062-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.</p>\",\"PeriodicalId\":19334,\"journal\":{\"name\":\"NPJ Aging and Mechanisms of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2021-05-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1038/s41514-021-00062-x\",\"citationCount\":\"9\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Aging and Mechanisms of Disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/s41514-021-00062-x\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Aging and Mechanisms of Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-021-00062-x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
引用次数: 9

摘要

过度磷酸化tau蛋白的异常积累诱导神经退行性疾病的发病机制,如阿尔茨海默病。具有肽基脯氨酸顺式/反式异构酶(PPIase)活性的分子伴侣已知可调节这些过程。此前,体外研究表明,52 kDa fk506结合蛋白(FKBP52)与tau相互作用,诱导其寡聚化和纤维形成,从而促进毒性。因此,我们假设FKBP52在tau转基因小鼠大脑中的表达增加会改变tau磷酸化和神经原纤维缠结的形成,最终导致记忆障碍。为了验证这一点,tau转基因(rTg4510)和野生型小鼠在双侧海马区注射过表达FKBP52病毒或GFP对照。我们检查了海马依赖性记忆、突触可塑性、tau磷酸化状态和神经元健康。这项研究表明,过度表达FKBP52的rTg4510小鼠空间学习受损,并伴有长期增强缺陷和海马神经元丢失,这与总caspase 12的适度增加有关。结合之前的研究,我们的发现表明FKBP52可能通过激活caspase依赖通路使神经元对tau介导的功能障碍敏感,从而导致记忆和学习障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FKBP52 overexpression accelerates hippocampal-dependent memory impairments in a tau transgenic mouse model.

Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer's disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that rTg4510 mice overexpressing FKBP52 had impaired spatial learning, accompanied by long-term potentiation deficits and hippocampal neuronal loss, which was associated with a modest increase in total caspase 12. Together with previous studies, our findings suggest that FKBP52 may sensitize neurons to tau-mediated dysfunction via activation of a caspase-dependent pathway, contributing to memory and learning impairments.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
NPJ Aging and Mechanisms of Disease
NPJ Aging and Mechanisms of Disease Medicine-Geriatrics and Gerontology
自引率
0.00%
发文量
0
审稿时长
8 weeks
期刊介绍: npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.
×
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:481959085
Book学术官方微信