Harbin Medical University Fourth Hospital, Neurology, Harbin, 150001, China.
Heilongjiang Provincial Hospital, Neurology, Harbin, Heilongjiang, 150030, China.
Cell Biol Int. 2020 Feb;44(2):630-636. doi: 10.1002/cbin.11263. Epub 2019 Nov 26.
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. However, its pathogenetic mechanism is still poorly understood. An increasing number of studies have evidenced the important role of long noncoding RNAs (lncRNAs) in AD. The aim of the current study was to investigate the effect and molecular mechanism of the lncRNA X-inactive specific transcript (XIST) in AD. Bilateral common carotid artery occlusion (2VO) was used to induce an AD model in mice. Hydrogen peroxide (H O ) was used to induce an AD model in N2a cells. The lncRNA XIST, miR-124, and BACE1 messenger RNA expression levels were detected by a real-time polymerase chain reaction. The BACE1 protein expression level was detected by western blot and immunofluorescence assay. The Aβ expression level was detected using an enzyme-linked immunosorbent assay kit. The expression level of lncRNA XIST was significantly upregulated in AD models, both in vivo and in vitro. Silencing of lncRNA XIST negatively regulated miR-124 and positively regulated BACE1 expression in N2a cells, which is attenuated by cotransfection of anti-miR-124 oligodeoxyribonucleotide (AMO-124). Silencing of lncRNA XIST reversed the effect of H O on miR-124, BACE1, and Aβ expression in N2a cells, which was reversed by cotransfection of AMO-124. Silencing of lncRNA XIST attenuated AD-related BACE1 alteration through miR-124. LncRNA XIST may be a new potential target for the treatment of AD.
阿尔茨海默病（AD）是一种慢性进行性神经退行性疾病。然而，其发病机制仍知之甚少。越来越多的研究表明长非编码 RNA（lncRNA）在 AD 中具有重要作用。本研究旨在探讨 lncRNA X 失活特异性转录物（XIST）在 AD 中的作用及分子机制。双侧颈总动脉闭塞（2VO）用于诱导小鼠 AD 模型。过氧化氢（H2O2）用于诱导 N2a 细胞 AD 模型。实时聚合酶链反应检测 lncRNA XIST、miR-124 和 BACE1 信使 RNA 的表达水平。Western blot 和免疫荧光法检测 BACE1 蛋白表达水平。酶联免疫吸附试验试剂盒检测 Aβ表达水平。AD 模型中，体内和体外 lncRNA XIST 的表达水平均显著上调。沉默 lncRNA XIST 负调控 N2a 细胞中 miR-124 的表达，正调控 BACE1 的表达，而反义 miR-124 寡核苷酸（AMO-124）共转染可减弱其作用。沉默 lncRNA XIST 逆转了 H2O2 对 N2a 细胞中 miR-124、BACE1 和 Aβ表达的影响，而 AMO-124 共转染则逆转了这一影响。沉默 lncRNA XIST 通过 miR-124 减弱 AD 相关的 BACE1 改变。lncRNA XIST 可能是治疗 AD 的新潜在靶点。
