Circular RNA APP contributes to Alzheimer's disease pathogenesis by modulating microglial polarization via miR-1906/CLIC1 axis.

IF 7.9 1区 医学 Q1 CLINICAL NEUROLOGY
Deng-Pan Wu, Yan-Su Wei, Li-Xiang Hou, Yu-Xuan Du, Qiu-Qing Yan, Ling-Ling Liu, Yuan-Dan Zhao, Ru-Yu Yan, Chao Yu, Zhen-Guo Zhong, Jin-Lan Huang
{"title":"Circular RNA APP contributes to Alzheimer's disease pathogenesis by modulating microglial polarization via miR-1906/CLIC1 axis.","authors":"Deng-Pan Wu, Yan-Su Wei, Li-Xiang Hou, Yu-Xuan Du, Qiu-Qing Yan, Ling-Ling Liu, Yuan-Dan Zhao, Ru-Yu Yan, Chao Yu, Zhen-Guo Zhong, Jin-Lan Huang","doi":"10.1186/s13195-025-01698-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Abnormal microglial polarization phenotypes contribute to the pathogenesis of Alzheimer's disease (AD). Circular RNAs (circRNAs) have garnered increasing attention due to their significant roles in human diseases. Although research has demonstrated differential expression of circRNAs in AD, their specific functions in AD pathogenesis remain largely unexplored.</p><p><strong>Methods: </strong>CircRNA microarray was performed to identify differentially expressed circRNAs in the hippocampus of APP/PS1 and WT mice. The stability of circAPP was assessed via RNase R treatment assay. CircAPP downstream targets miR-1906 and chloride intracellular channel 1 (CLIC1) were identified using bioinformatics and proteomics, respectively. RT-PCR assay was conducted to detect the expression of circAPP, miR-1906 and CLIC1. Morris water maze (MWM) test, passive avoidance test and novel object recognition task were used to detect cognitive function of APP/PS1 mice. Microglial M1/M2 polarization and AD pathology were assessed using Western blot, flow cytometry and Golgi staining assays. CLIC1 expression and channel activity were evaluated using Western blot and functional chloride channel assays, respectively. The subcellular location of circAPP was assessed via FISH and RT-PCR assays. RNA pull-down assay was performed to detect the interaction of miR-1906 with circAPP and 3' untranslated region (3'UTR) of CLIC1 mRNA.</p><p><strong>Results: </strong>In this study, we identified a novel circRNA, named circAPP, that is encoded by amyloid precursor protein (APP) and is implicated in AD. CircAPP is a stable circRNA that was upregulated in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice. Downregulation of circAPP or CLIC1, or overexpression of miR-1906 in microglia modulated microglial M1/M2 polarization in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice, and improved AD pathology and the cognitive function of APP/PS1 mice. Further results revealed that circAPP was mainly distributed in the cytoplasm, and circAPP could regulate CLIC1 expression and channel activity by interacting with miR-1906 and affecting miR-1906 expression, thereby regulating microglial polarization in AD.</p><p><strong>Conclusions: </strong>Taken together, our study elucidates the regulatory role of circAPP in AD microglial polarization via miR-1906/CLIC1 axis, and suggests that circAPP may act as a critical player in AD pathogenesis and represent a promising therapeutic target for AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"44"},"PeriodicalIF":7.9000,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829462/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's Research & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13195-025-01698-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Abnormal microglial polarization phenotypes contribute to the pathogenesis of Alzheimer's disease (AD). Circular RNAs (circRNAs) have garnered increasing attention due to their significant roles in human diseases. Although research has demonstrated differential expression of circRNAs in AD, their specific functions in AD pathogenesis remain largely unexplored.

Methods: CircRNA microarray was performed to identify differentially expressed circRNAs in the hippocampus of APP/PS1 and WT mice. The stability of circAPP was assessed via RNase R treatment assay. CircAPP downstream targets miR-1906 and chloride intracellular channel 1 (CLIC1) were identified using bioinformatics and proteomics, respectively. RT-PCR assay was conducted to detect the expression of circAPP, miR-1906 and CLIC1. Morris water maze (MWM) test, passive avoidance test and novel object recognition task were used to detect cognitive function of APP/PS1 mice. Microglial M1/M2 polarization and AD pathology were assessed using Western blot, flow cytometry and Golgi staining assays. CLIC1 expression and channel activity were evaluated using Western blot and functional chloride channel assays, respectively. The subcellular location of circAPP was assessed via FISH and RT-PCR assays. RNA pull-down assay was performed to detect the interaction of miR-1906 with circAPP and 3' untranslated region (3'UTR) of CLIC1 mRNA.

Results: In this study, we identified a novel circRNA, named circAPP, that is encoded by amyloid precursor protein (APP) and is implicated in AD. CircAPP is a stable circRNA that was upregulated in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice. Downregulation of circAPP or CLIC1, or overexpression of miR-1906 in microglia modulated microglial M1/M2 polarization in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice, and improved AD pathology and the cognitive function of APP/PS1 mice. Further results revealed that circAPP was mainly distributed in the cytoplasm, and circAPP could regulate CLIC1 expression and channel activity by interacting with miR-1906 and affecting miR-1906 expression, thereby regulating microglial polarization in AD.

Conclusions: Taken together, our study elucidates the regulatory role of circAPP in AD microglial polarization via miR-1906/CLIC1 axis, and suggests that circAPP may act as a critical player in AD pathogenesis and represent a promising therapeutic target for AD.

环状RNA APP通过miR-1906/CLIC1轴调节小胶质细胞极化参与阿尔茨海默病的发病机制。
背景:异常的小胶质细胞极化表型与阿尔茨海默病(AD)的发病机制有关。环状rna (circRNAs)因其在人类疾病中的重要作用而受到越来越多的关注。尽管研究已经证实circRNAs在AD中的差异表达,但它们在AD发病机制中的具体功能在很大程度上仍未被探索。方法:应用CircRNA芯片技术鉴定APP/PS1和WT小鼠海马区差异表达的CircRNA。通过RNase R处理实验评估circAPP的稳定性。CircAPP下游靶点miR-1906和氯离子胞内通道1 (CLIC1)分别通过生物信息学和蛋白质组学进行鉴定。RT-PCR检测circAPP、miR-1906、CLIC1的表达。采用Morris水迷宫(MWM)测试、被动回避测试和新物体识别任务检测APP/PS1小鼠的认知功能。采用Western blot、流式细胞术和高尔基染色法检测小胶质细胞M1/M2极化和AD病理。分别用Western blot和功能性氯离子通道法评估CLIC1的表达和通道活性。通过FISH和RT-PCR测定circAPP的亚细胞位置。采用RNA下拉法检测miR-1906与circAPP和CLIC1 mRNA 3‘非翻译区(3’ utr)的相互作用。结果:在这项研究中,我们发现了一种名为circAPP的新型环状rna,它由淀粉样蛋白前体蛋白(APP)编码,与AD有关。CircAPP是一种稳定的环状rna,在a β处理的APP/PS1小鼠的小胶质细胞和海马中表达上调。在小胶质细胞中下调circAPP或CLIC1,或过表达miR-1906可调节a β处理的APP/PS1小鼠小胶质细胞和海马的小胶质M1/M2极化,改善APP/PS1小鼠AD病理和认知功能。进一步的结果显示circAPP主要分布在细胞质中,circAPP通过与miR-1906相互作用,影响miR-1906的表达,调节CLIC1的表达和通道活性,从而调节AD小胶质细胞的极化。综上所述,我们的研究阐明了circAPP通过miR-1906/CLIC1轴对AD小胶质细胞极化的调节作用,并提示circAPP可能在AD的发病机制中发挥关键作用,并代表了AD的有希望的治疗靶点。
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
Alzheimer's Research & Therapy
Alzheimer's Research & Therapy 医学-神经病学
CiteScore
13.10
自引率
3.30%
发文量
172
审稿时长
>12 weeks
期刊介绍: Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.
×
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