CircAXL Knockdown Alleviates Aβ(1-42)-Induced Neurotoxicity in Alzheimer’s Disease via Repressing PDE4A by Releasing miR-1306-5p

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 (Aβ(1-42)). 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 Aβ(1-42)-treated SK-N-SH cells. CircAXL knockdown alleviated Aβ(1-42)-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 Aβ(1-42)-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 Aβ(1-42)-induced neurotoxicity in AD pathology via repressing PDE4A by releasing miR-1306-5p. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11064-022-03563-7.