Department of Anatomy, Basic Medical College, Shaanxi University of Chinese Medicine, Xianyang, 712046, Shaanxi Province, People's Republic of China.
Discipline Innovation Team of Shaanxi, University of Chinese Medicine, Xianyang, 712046, Shaanxi Province, People's Republic of China.
Neurochem Res. 2023 Sep;48(9):2895-2910. doi: 10.1007/s11064-023-03944-6. Epub 2023 May 23.
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the world, which seriously affects AD patients' life quality. Recently, long non-coding RNAs (lncRNAs) have been reported to play a key role in AD pathogenesis, however, the specific mechanism remains unclear. Herein, we aimed to investigate the role of lncRNA NKILA in AD. The learning and memory performance of rats from streptozotocin (STZ)-treated or other treated groups were tested by Morris water maze test. Relative levels of genes and proteins were measured using RT-qPCR and Western blotting. Mitochondrial membrane potential was tested by JC-1 staining. Levels of ROS, SOD, MDA, GSH-Px, and LDH were measured using corresponding commercial kits. Apoptosis was evaluated by TUNEL staining or Flow cytometry assay. RNA Immunoprecipitation (RIP), RNA pulldown, Chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were utilized to test the interaction between indicated molecules. STZ treatment caused learning and memory impairment in rats and oxidative stress damage in SH-SY5Y cells. LncRNA NKILA was found to be elevated in the hippocampal tissues of rats and SH-SY5Y cells after STZ exposure. Knockdown of lncRNA NKILA alleviated STZ-induced neuronal damage. Furthermore, lncRNA NKILA could bind to ELAVL1, which regulate the stability of FOXA1 mRNA. Moreover, TNFAIP1 transcription process was controlled by FOXA1, which targeted the promoter of TNFAIP1. In vivo results demonstrated that lncRNA NKILA accelerated STZ-induced neuronal damage and oxidative stress by FOXA1/TNFAIP1 axis. Our findings indicated that knockdown of lncRNA NKILA inhibited the neuronal damage and oxidative stress induced by STZ through the FOXA1/TNFAIP1 axis, thereby alleviating the development of AD, revealing a promising therapeutic axis for AD treatment.
阿尔茨海默病（AD）是世界上最常见的神经退行性疾病之一，严重影响 AD 患者的生活质量。最近，长链非编码 RNA（lncRNA）被报道在 AD 发病机制中发挥关键作用，然而，具体机制尚不清楚。在此，我们旨在研究 lncRNA NKILA 在 AD 中的作用。通过 Morris 水迷宫试验测试链脲佐菌素（STZ）处理或其他处理组大鼠的学习和记忆表现。使用 RT-qPCR 和 Western blot 测量基因和蛋白质的相对水平。通过 JC-1 染色测试线粒体膜电位。使用相应的商业试剂盒测量 ROS、SOD、MDA、GSH-Px 和 LDH 的水平。通过 TUNEL 染色或流式细胞术评估细胞凋亡。利用 RNA 免疫沉淀（RIP）、RNA 下拉、染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测等方法检测指示分子之间的相互作用。STZ 处理导致大鼠学习和记忆受损以及 SH-SY5Y 细胞氧化应激损伤。发现在 STZ 暴露后大鼠海马组织和 SH-SY5Y 细胞中 lncRNA NKILA 升高。lncRNA NKILA 敲低减轻了 STZ 诱导的神经元损伤。此外，lncRNA NKILA 可以与 ELAVL1 结合，调节 FOXA1 mRNA 的稳定性。此外，TNFAIP1 的转录过程受 FOXA1 控制，FOXA1 靶向 TNFAIP1 的启动子。体内结果表明，lncRNA NKILA 通过 FOXA1/TNFAIP1 轴加速 STZ 诱导的神经元损伤和氧化应激。我们的研究结果表明，通过 FOXA1/TNFAIP1 轴，lncRNA NKILA 敲低抑制 STZ 诱导的神经元损伤和氧化应激，从而缓解 AD 的发展，为 AD 治疗提供了有前途的治疗靶点。
