Data_Sheet_1_Targeting MicroRNA-125b Promotes Neurite Outgrowth but Represses Cell Apoptosis and Inflammation via Blocking PTGS2 and CDK5 in a FOXQ1-Dependent Way in Alzheimer Disease.pdf

This study aimed to explore the molecular regulatory network among microRNA-125b (miR-125b), forkhead box Q1 (FOXQ1), prostaglandin-endoperoxide synthase 2 (PTGS2), and cyclin-dependent kinase 5 (CDK5), as well as their effects on cell apoptosis, neurite outgrowth, and inflammation in Alzheimer disease (AD). Rat embryo cerebral cortex neurons and nerve growth factor–stimulated PC12 cells were insulted by Aβ1−42 to construct two AD cellular models. Negative control (NC) inhibitor, miR-125b inhibitor, NC siRNA, FOXQ1 siRNA, PTGS2 siRNA, and CDK5 siRNA were transferred into the two AD cellular models alone or combined. Then, cell apoptosis, neurite outgrowth, proinflammatory cytokines, miR-125b, FOXQ1, PTGS2, and CDK5 expressions were detected. MiR-125b inhibition facilitated neurite outgrowth but suppressed cell apoptosis and proinflammatory cytokines (tumor necrosis factor-α, interleukin 1β, and interleukin 6); meanwhile, it upregulated FOXQ1 but downregulated PTGS2 and CDK5. Furthermore, FOXQ1 inhibition promoted cell apoptosis and proinflammatory cytokines but repressed neurite outgrowth; PTGS2 inhibition achieved the opposite effects; CDK5 inhibition attenuated cell apoptosis, whereas it less affected neurite outgrowth and inflammation. Notably, FOXQ1 inhibition attenuated, whereas PTGS2 inhibition elevated the effect of miR-125b inhibition on regulating neurite outgrowth, cell apoptosis, and proinflammatory cytokines. As for CDK5 inhibition, it enhanced the effect of miR-125b inhibition on regulating cell apoptosis, but less impacted the neurite outgrowth and proinflammatory cytokines. Additionally, PTGS2 inhibition and CDK5 inhibition both reversed the effect of FOXQ1 inhibition on regulating cell apoptosis, neurite outgrowth, and proinflammatory cytokines. In conclusion, targeting miR-125b alleviates AD progression via blocking PTGS2 and CDK5 in a FOXQ1-dependent way.

本研究旨在探究miR-125b（微小RNA-125b）、FOXQ1（叉头框Q1）、PTGS2（前列腺素-内过氧化物合酶2）以及CDK5（细胞周期依赖性激酶5）之间的分子调控网络，及其对阿尔茨海默病（AD）中细胞凋亡、神经突起生长和炎症的影响。本研究采用大鼠胚胎大脑皮层神经元和神经生长因子激活的PC12细胞，通过给予Aβ1−42进行损伤，构建了两种AD细胞模型。单独或联合转染阴性对照抑制剂、miR-125b抑制剂、阴性siRNA、FOXQ1 siRNA、PTGS2 siRNA和CDK5 siRNA至两种AD细胞模型中。随后，检测了细胞凋亡、神经突起生长、促炎细胞因子、miR-125b、FOXQ1、PTGS2和CDK5的表达。miR-125b的抑制促进了神经突起生长，但抑制了细胞凋亡和促炎细胞因子（肿瘤坏死因子-α、白细胞介素1β和白细胞介素6）的表达；同时，它上调了FOXQ1的表达，而下调了PTGS2和CDK5的表达。此外，FOXQ1的抑制促进了细胞凋亡和促炎细胞因子的表达，但抑制了神经突起生长；PTGS2的抑制产生了相反的效果；CDK5的抑制减轻了细胞凋亡，而对神经突起生长和炎症的影响较小。值得注意的是，FOXQ1的抑制减弱了，而PTGS2的抑制增强了miR-125b抑制对调控神经突起生长、细胞凋亡和促炎细胞因子的作用。至于CDK5的抑制，它增强了miR-125b抑制对调控细胞凋亡的作用，但对神经突起生长和促炎细胞因子的影响较小。此外，PTGS2的抑制和CDK5的抑制均逆转了FOXQ1抑制对调控细胞凋亡、神经突起生长和促炎细胞因子的作用。综上所述，靶向miR-125b通过阻断PTGS2和CDK5，以FOXQ1依赖的方式减缓了AD的进展。