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.

Jingcong Zhuang,Pingping Cai,Huili Yang,Rong Wang,Renjing Zhu,Qingwei Yang,Longling Li,Zhongjie Chen

doi:10.3389/fncel.2020.587747

Abstract

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.

Highlights

Alzheimer disease (AD) represents a devastating, age-related neurodegenerative disease with a long asymptomatic preclinical phase and an average clinical duration of 10 years, affecting ∼35 million individuals worldwide (Masters et al, 2015; Liu et al, 2019)
One previous study conducted by our collaborate institution discloses that miR-125b participates in regulating the pathogenesis of AD, forkhead box Q1 (FOXQ1), prostaglandin-endoperoxide synthase 2 (PTGS2), and cyclin-dependent kinase 5 (CDK5) expressions in AD cellular models (Ma et al, 2019)
The effect of Aβ1−42 treatment on FOXQ1, PTGS2, and CDK5 expression and cell activities was evaluated. In both primary neurons (Supplementary Figures 1A–F, 2A–C) and NGFstimulated PC-12 cells (Supplementary Figures 1G–L, 2D–F), FOXQ1 expression and neurite outgrowth were decreased, while PTGS2 and CDK5 expressions, cell apoptosis, and inflammation were increased in AD models compared with normal cells

Summary

Introduction

Alzheimer disease (AD) represents a devastating, age-related neurodegenerative disease with a long asymptomatic preclinical phase (more than 20 years) and an average clinical duration of 10 years, affecting ∼35 million individuals worldwide (Masters et al, 2015; Liu et al, 2019). It is characterized by major pathological hallmarks in the brain including the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles (Gjoneska et al, 2015). The molecular regulatory network among miR-125b, FOXQ1, PTGS2, and CDK5, as well as their regulatory effects on the functions of AD cellular models, is not evaluated yet

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Methods

Results