Department of Pharmacy, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Department of Pharmacy, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China; Department of Pharmacy, People's Hospital of Henan University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, China.
School of Clinical Medicine, The First Affiliated Hospital of Henan University of Science and Technology, Henan University of Science and Technology, Luoyang, Henan, China.
Neuroscience. 2023 Oct 1;529:88-98. doi: 10.1016/j.neuroscience.2023.02.016. Epub 2023 Jun 5.
Long noncoding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1) is closely implicated in neurological diseases, while its implication in Alzheimer's disease (AD) is rarely reported. This study aimed to investigate the effect of lnc-NEAT1 knockdown on neuron injury, inflammation, and oxidative stress in AD, as well as its interaction with downstream targets and pathways. APPswe/PS1dE9 transgenic mice were injected with negative control or lnc-NEAT1 interference lentivirus. Besides, AD cellular model was constructed by amyloid β treatment in mice primary neuron cells; then, knockdown of lnc-NEAT1 and microRNA-193a was performed alone or in combination. In vivo experiments revealed that Lnc-NEAT1 knockdown improved cognition in AD mice reflected by Morrison water maze and Y-maze assays. Besides, lnc-NEAT1 knockdown reduced injury and apoptosis, decreased inflammatory cytokine levels, repressed oxidative stress level, and activated adenosine cyclophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (NRF2)/nicotinamide adenine dinucleotide phosphate dehydrogenase 1 (NQO1) pathways in hippocampi of AD mice. Notably, lnc-NEAT1 down-regulated microRNA-193a both in vitro and in vivo and acted as a decoy of microRNA-193a. In vitro experiments showed that lnc-NEAT1 knockdown decreased apoptosis and oxidative stress, improved cell viability, also activated CREB/BDNF and NRF2/NQO1 pathways in AD cellular model. Meanwhile, microRNA-193a knockdown showed the opposite effects, which also attenuated lnc-NEAT1 knockdown-mediated reduction in injury, oxidative stress, and CREB/BDNF and NRF2/NQO1 pathways of AD cellular model. In conclusion, lnc-NEAT1 knockdown reduces neuron injury, inflammation, and oxidative stress through activating microRNA-193a mediated CREB/BDNF and NRF2/NQO1 pathways in AD.
长链非编码 RNA 核富集丰富转录本 1（lnc-NEAT1）与神经退行性疾病密切相关，但其在阿尔茨海默病（AD）中的作用鲜有报道。本研究旨在探讨 lnc-NEAT1 敲低对 AD 神经元损伤、炎症和氧化应激的影响，以及其与下游靶标和通路的相互作用。APPswe/PS1dE9 转基因小鼠注射阴性对照或 lnc-NEAT1 干扰慢病毒。此外，通过在小鼠原代神经元细胞中用淀粉样 β 处理构建 AD 细胞模型，然后单独或联合进行 lnc-NEAT1 和 microRNA-193a 的敲低。体内实验表明，lnc-NEAT1 敲低改善了 AD 小鼠的认知功能，表现在 Morris 水迷宫和 Y 迷宫实验中。此外，lnc-NEAT1 敲低减少了 AD 小鼠海马区的损伤和凋亡，降低了炎症细胞因子水平，抑制了氧化应激水平，激活了环磷酸腺苷反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）和核因子红细胞 2 相关因子 2（NRF2）/烟酰胺腺嘌呤二核苷酸磷酸脱氢酶 1（NQO1）通路。值得注意的是，lnc-NEAT1 在体外和体内均下调了 microRNA-193a，并作为 microRNA-193a 的诱饵。体外实验表明，lnc-NEAT1 敲低减少了 AD 细胞模型的凋亡和氧化应激，提高了细胞活力，也激活了 CREB/BDNF 和 NRF2/NQO1 通路。同时，microRNA-193a 敲低表现出相反的效果，也减弱了 AD 细胞模型中 lnc-NEAT1 敲低介导的损伤、氧化应激以及 CREB/BDNF 和 NRF2/NQO1 通路的减少。综上所述，lnc-NEAT1 通过激活 microRNA-193a 介导的 CREB/BDNF 和 NRF2/NQO1 通路，减少 AD 中的神经元损伤、炎症和氧化应激。
