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LINC00094/miR-224-5p（miR-497-5p）/Endophilin-1 轴在盐酸美金刚介导的 AD 微环境下对血脑屏障保护作用中的作用。

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.

机构信息

Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China.

Department of Neurobiology, School of Life Sciences, China Medical University, Shenyang, China.

出版信息

J Cell Mol Med. 2019 May;23(5):3280-3292. doi: 10.1111/jcmm.14214. Epub 2019 Feb 22.

DOI:10.1111/jcmm.14214
PMID:30801976
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6484416/
Abstract

The dysfunction of the blood-brain barrier (BBB) is one of the main pathological features of Alzheimer's disease (AD). Memantine (MEM), an N-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 Abeta -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.

摘要

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。作为一种 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，美金刚（MEM）已被广泛报道用于 AD 治疗。本研究旨在阐明 MEM 在调节 AD 微环境中 BBB 通透性中的作用及其可能的机制。本研究表明，LINC00094 在体外 BBB 模型中 Abeta 孵育的微血管内皮细胞（EC）中显著增加。此外，MEM 孵育的 EC 中其含量降低。沉默 LINC00094 可显著降低 BBB 通透性，同时上调 ZO-1、occludin 和 claudin-5 的表达。此外，沉默 LINC00094 增强了 MEM 在 AD 微环境中降低 BBB 通透性的作用。机制分析表明，降低 LINC00094 通过上调 miR-224-4p/miR-497-5p 抑制内收蛋白-1 的表达，促进 ZO-1、occludin 和 claudin-5 的表达，最终减轻 AD 微环境中的 BBB 通透性。综上所述，本研究表明，MEM/LINC00094/miR-224-5p（miR-497-5p）/内收蛋白-1 轴在 AD 微环境中 BBB 通透性的调节中起着关键作用。沉默 LINC00094 联合 MEM 为 AD 的治疗提供了一个新的靶点。

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