lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer's disease.

IF 1.8 4区 医学 Q3 GENETICS & HEREDITY Journal of neurogenetics Pub Date : 2022-03-01 Epub Date: 2022-01-31 DOI:10.1080/01677063.2022.2028784
Xi-Wu Yan, Huai-Jun Liu, Yu-Xing Hong, Ting Meng, Jun Du, Cheng Chang
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引用次数: 14

Abstract

Alzheimer's disease (AD) is the leading cause of dementia globally, but effective treatment is lacking. We aimed to explore lncRNA XIST role in AD and the mechanisms involved in the effect of changes in lncRNA XIST on the expression of Aβ-degrading enzymes. The mouse model of AD and the cell model induced by Aβ were established. LncRNA XIST, IDE, NEP, Plasmin, ACE, EZH2 expressions and distribution of XIST in the nucleus and cytoplasm were detected by qRT-PCR. Inflammatory cytokines IL-6, IL-1β, TNFα, IL-8, and Aβ42 levels were detected by ELISA. TUNEL was used to measure brain tissue damage. Cell proliferation was detected by CCK-8 assay. Flow cytometry detected cell apoptosis. RIP validated the combination of XIST and EZH2. ChIP verified that XIST recruits EZH2 to mediate enrichment of HEK27me3 in the NEP promoter region. The protein expression in brain tissues and cells was detected by Western blot. The expression of lncRNA XIST was increased in AD mice and cell models. Inflammation and injury of nerve cells occurred in AD mice and cell models. The knockdown of lncRNA XIST alleviated Aβ-induced neuronal inflammation and damage. LncRNA XIST affected the expression of Aβ-degrading enzyme NEP, and lncRNA XIST was negatively correlated with NEP expression in AD mice. LncRNA XIST regulated NEP expression partly through epigenetic regulation by binding with EZH2. LncRNA XIST mediated neuronal inflammation and injury through epigenetic regulation of NEP. Overall, our study found that lncRNA XIST induced Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in AD.

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lncRNA XIST通过NEP在阿尔茨海默病中的表观遗传抑制诱导Aβ积累和神经炎症。
阿尔茨海默病(AD)是全球痴呆症的主要原因,但缺乏有效的治疗方法。我们旨在探讨lncRNA XIST在AD中的作用,以及lncRNA XIST改变对a β-降解酶表达影响的机制。建立小鼠AD模型和Aβ诱导的细胞模型。采用qRT-PCR检测LncRNA XIST、IDE、NEP、Plasmin、ACE、EZH2在细胞核和细胞质中的表达和分布。ELISA法检测各组炎症因子IL-6、IL-1β、TNFα、IL-8、a - β42水平。TUNEL用于测量脑组织损伤。CCK-8法检测细胞增殖。流式细胞术检测细胞凋亡。RIP验证了XIST和EZH2的结合。ChIP证实XIST招募EZH2介导NEP启动子区域HEK27me3的富集。Western blot检测脑组织及细胞蛋白表达。lncRNA XIST在AD小鼠和细胞模型中表达升高。AD小鼠和细胞模型均出现神经细胞炎症和损伤。lncRNA XIST的下调可减轻a β诱导的神经元炎症和损伤。LncRNA XIST影响a β-降解酶NEP的表达,且LncRNA XIST与AD小鼠NEP表达呈负相关。LncRNA XIST部分通过与EZH2结合的表观遗传调控调控NEP的表达。LncRNA XIST通过NEP的表观遗传调控介导神经元炎症和损伤。总的来说,我们的研究发现lncRNA XIST通过表观遗传抑制NEP在AD中诱导Aβ积累和神经炎症。
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来源期刊
Journal of neurogenetics
Journal of neurogenetics 医学-神经科学
CiteScore
4.40
自引率
0.00%
发文量
13
审稿时长
>12 weeks
期刊介绍: The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms
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