CircAXL Knockdown Alleviates Aβ1-42-Induced Neurotoxicity in Alzheimer’s Disease via Repressing PDE4A by Releasing miR-1306-5p

Shengxi Meng,Bing Wang,Wentao Li

doi:10.1007/s11064-022-03563-7

Abstract

The development of Alzheimer’s disease (AD) is implicated with the dysregulation of numerous circular RNAs (circRNAs). However, the function of several circRNAs remains unclear. The aim of this study was to investigate the role of circular AXL receptor tyrosine kinase (circAXL) in AD. Cell models of AD were constructed by treating SK-N-SH cells with amyloid-β (Aβ1-42). The expression of circAXL, miR-1306-5p and phosphodiesterase 4A (PDE4A) mRNA was detected by quantitative real-time PCR (qPCR). Cell viability was checked by CCK-8 assay. The production of inflammatory factors was monitored by ELISA. Cell apoptosis was checked by flow cytometry assay. Oxidative stress was assessed by ROS level, MDA level and SOD activity using commercial kits. Endoplasmic reticulum (ER) stress was assessed by ER-related protein markers using western blotting. The relationship between miR-1306-5p and circAXL or PDE4A was validated by RIP assay and dual-luciferase reporter assay. Serum exosomes were isolated by centrifugation to assess the diagnostic value of exosomal circAXL, miR-1306-5p and PDE4A. CircAXL was overexpressed in Aβ1-42-treated SK-N-SH cells. CircAXL knockdown alleviated Aβ1-42-induced cell cytotoxicity, cell apoptosis, inflammation, oxidative stress and endoplasmic reticulum (ER) stress in SK-N-SH cells. MiR-1306-5p was screened as a target of circAXL, and miR-1306-5p inhibition abolished the effects of circAXL knockdown. MiR-1306-5p inhibited the expression of PDE4A, and circAXL regulated PDE4A expression by targeting miR-1306-5p. MiR-1306-5p restoration also alleviated Aβ1-42-induced cell injuries, while PDE4A reintroduction abolished the effects of miR-1306-5p restoration. Exosomal circAXL and exosomal miR-1306-5p had diagnostic values for AD. CircAXL knockdown alleviates Aβ1-42-induced neurotoxicity in AD pathology via repressing PDE4A by releasing miR-1306-5p.

Highlights

Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the most common form of dementia, characterized by memory impairment and cognitive decline [1]
Among the target genes of miR-1306-5p predicted by targetscan, we found that phosphodiesterase 4A (PDE4A), a key regulator of cyclic adenosine monophosphate (cAMP) degradation rate, was notably upregulated in Aβ1-42-treated SK-N-SH cells, in a dose-dependent manner (Fig. 5A and Fig. S1C)
The results mainly discovered that the knockdown of circular AXL receptor tyrosine kinase (circAXL) largely inhibited Aβ1-42-induced neuron injuries, including cell cytotoxicity, cell apoptosis, inflammation, oxidative stress and endoplasmic reticulum (ER) stress in SKN-SH cells

Summary

Introduction

Alzheimer’s disease (AD), a progressive neurodegenerative disease, is the most common form of dementia, characterized by memory impairment and cognitive decline [1]. AD has longer asymptomatic preclinical features, and individuals with normal cognition can suffer from the disease [2]. It is estimated that the prevalence rate for people over 65 years old is 13%, and the prevalence rate for people over 75 years. Circular RNAs (circRNAs) are a group of closed-loop, noncoding RNA molecules, with enormous regulatory potential in human diseases. CircRNAs express high stability in mammalian cells due to the lack of 5′ cap and 3′ tail [6]. Emerging studies discover that circRNA deregulation is associated with the initiation and development of human neurological diseases [7]. Circ_0067835 was involved in temporal lobe epilepsy, and poor circ_0067835

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