长链非编码 RNA MALAT1 通过抑制神经元凋亡和神经炎症而刺激神经突生长，其与 miR-125b 的相关性介导阿尔茨海默病中的 PTGS2、CDK5 和 FOXQ1。

Long Non-coding RNA MALAT1 Inhibits Neuron Apoptosis and Neuroinflammation While Stimulates Neurite Outgrowth and Its Correlation With MiR-125b Mediates PTGS2, CDK5 and FOXQ1 in Alzheimer's Disease.

机构信息

Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou, China.

Department of Pharmacy, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.

出版信息

Curr Alzheimer Res. 2019;16(7):596-612. doi: 10.2174/1567205016666190725130134.

DOI:10.2174/1567205016666190725130134

PMID:31345147

Abstract

BACKGROUND

This study aimed to investigate the effect of long noncoding ribonucleic acids (RNAs) metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1) on regulating neuron apoptosis, neurite outgrowth and inflammation, and further explore its molecule mechanism in Alzheimer's disease (AD).

METHODS

Control overexpression, lnc-MALAT1 overexpression, control shRNA, and lnc-MALAT1 shRNA were transfected into NGF-stimulated PC12 cellular AD model and cellular AD model from primary cerebral cortex neurons of rat embryo, which were established by Aβ1-42 insult. Rescue experiments were performed by transferring lnc-MALAT1 overexpression and lnc-MALAT1 overexpression & miR-125b overexpression plasmids. Neuron apoptosis, neurite outgrowth and inflammation were detected by Hoechst-PI/apoptosis marker expressions, and observations were made using microscope and RT-qPCR/Western blot assays. PTGS2, CDK5 and FOXQ1 expressions in rescue experiments were also determined.

RESULTS

In two AD models, lnc-MALAT1 overexpression inhibited neuron apoptosis, promoted neurite outgrowth, reduced IL-6 and TNF-α levels, and increased IL-10 level compared to control overexpression, while lnc-MALAT1 knockdown promoted neuron apoptosis, repressed neurite outgrowth, elevated IL-6 and TNF-α levels, but reduced IL-10 level compared to control shRNA. Additionally, lnc- MALAT1 reversely regulated miR-125b expression, while miR-125b did not influence the lnc- MALAT1 expression. Subsequently, rescue experiments revealed that miR-125b induced neuron apoptosis, inhibited neurite outgrowth and promoted inflammation, also increased PTGS2 and CDK5 expressions but decreased FOXQ1 expression in lnc-MALAT1 overexpression treated AD models.

CONCLUSION

Lnc-MALAT1 might interact with miR-125b to inhibit neuron apoptosis and inflammation while promote neurite outgrowth in AD.

摘要

背景

本研究旨在探讨长非编码 RNA（lncRNAs）转移相关肺腺癌转录物 1（lnc-MALAT1）对调节神经元凋亡、轴突生长和炎症的影响，并进一步探讨其在阿尔茨海默病（AD）中的分子机制。

方法

将对照过表达、lnc-MALAT1 过表达、对照 shRNA 和 lnc-MALAT1 shRNA 转染到 NGF 刺激的 PC12 细胞 AD 模型和原代大鼠胚胎大脑皮质神经元建立的细胞 AD 模型中，通过 Aβ1-42 损伤。通过转移 lnc-MALAT1 过表达和 lnc-MALAT1 过表达和 miR-125b 过表达质粒进行挽救实验。通过 Hoechst-PI/凋亡标志物表达检测神经元凋亡、轴突生长和炎症，并用显微镜和 RT-qPCR/Western blot 检测观察。还测定了挽救实验中 PTGS2、CDK5 和 FOXQ1 的表达。

结果

在两个 AD 模型中，与对照过表达相比，lnc-MALAT1 过表达抑制神经元凋亡，促进轴突生长，降低 IL-6 和 TNF-α水平，增加 IL-10 水平，而 lnc-MALAT1 敲低促进神经元凋亡，抑制轴突生长，升高 IL-6 和 TNF-α水平，但降低 IL-10 水平与对照 shRNA 相比。此外，lnc-MALAT1 反向调节 miR-125b 的表达，而 miR-125b 不影响 lnc-MALAT1 的表达。随后，挽救实验表明，miR-125b 在 lnc-MALAT1 过表达处理的 AD 模型中诱导神经元凋亡，抑制轴突生长并促进炎症，还增加了 PTGS2 和 CDK5 的表达，但降低了 FOXQ1 的表达。