The role of LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 axis in Memantine mediated protective effects on blood-brain barrier in AD microenvironment
The role of LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 axis in Memantine mediated protective effects on blood-brain barrier in AD microenvironment
复制标题
LINC00094/miR-224-5p (miR-497-5p)/Endophilin-1 轴在美金刚介导的 AD 微环境血脑屏障保护作用中的作用
DOI：
10.1111/jcmm.14214
复制
发表时间：
2019
影响因子：
5.3
通讯作者：
Shang Xiuli
中科院分区：
文献类型：
--
作者：
Zhu Lu;Lin Meiqing;Ma Jun;Liu Wenjing;Gao Lili;Wei Shanshan;Xue Yixue;Shang Xiuli
血脑屏障（BBB）功能障碍是阿尔茨海默病（AD）的主要病理特征之一。美金刚（Memantine，MEM）是一种N-甲基-d-天冬氨酸（N-methyl-d-aspartate，NMDA）受体拮抗剂，已被广泛应用于AD的治疗。本研究旨在证明MEM在AD微环境中调节BBB通透性的作用及其可能的机制。本研究表明，LINC 00094在体外A β 1 - 42-孵育的BBB模型微血管内皮细胞（EC）中显著增加。此外，在MEM孵育的EC中其降低。沉默LINC 00094显著降低BBB通透性，同时上调ZO-1、occludin和claudin-5的表达。此外，沉默LINC 00094增强了MEM降低AD微环境中BBB通透性的作用。机制分析表明，降低LINC 00094通过上调miR-224 - 4p/miR-497 - 5 p抑制Endophilin-1表达，促进ZO-1、occludin和claudin-5表达，最终减轻AD微环境中BBB通透性。综上所述，本研究表明MEM/LINC 00094/miR-224 - 5 p（miR-497 - 5 p）/Endophilin-1轴在AD微环境中BBB通透性的调节中起着至关重要的作用。沉默LINC 00094与MEM联合为AD的治疗提供了新的靶点。
The dysfunction of the blood‐brain barrier (BBB) is one of the main pathological features of Alzheimer's disease (AD). Memantine (MEM), anN‐methyl‐d‐aspartate (NMDA) receptor antagonist, has been reported that been used widely for AD therapy. This study was performed to demonstrate the role of the MEM in regulating BBB permeability in AD microenvironment as well as its possible mechanisms. The present study showed that LINC00094 was dramatically increased in Abeta1‐42‐incubated microvascular endothelial cells (ECs) of BBB model in vitro. Besides, it was decreased in MEM‐incubated ECs. Silencing LINC00094 significantly decreased BBB permeability, meanwhile up‐regulating the expression of ZO‐1, occludin and claudin‐5. Furthermore, silencing LINC00094 enhance the effect of MEM on decreasing BBB permeability in AD microenvironment. The analysis of the mechanism demonstrated that reduction of LINC00094 inhibited Endophilin‐1 expression by up‐regulating miR‐224‐4p/miR‐497‐5p, promoted the expression of ZO‐1, occludin and claudin‐5, and ultimately alleviated BBB permeability in AD microenvironment. Taken together, the present study suggests that the MEM/LINC00094/miR‐224‐5p (miR‐497‐5p)/Endophilin‐1 axis plays a crucial role in the regulation of BBB permeability in AD microenvironment. Silencing LINC00094 combined with MEM provides a novel target for the therapy of AD.