Circ_0002945 functions as a competing endogenous RNA to promote Aβ25-35-induced endoplasmic reticulum stress and apoptosis in SK-N-SH cells and human primary neurons

Background:Circular RNAs (circRNAs) have been shown to function as competing endogenous RNAs (ceRNAs) to participate in the pathogenesis of Alzheimer's disease (AD). In this study, we set to identify the activity and mechanism of circ_0002945 in AD pathogenesis.

Methods:The levels of circ_0002945, microRNA (miR)-431-5p and TNF alpha induced protein 1 (TNFAIP1) were measured by quantitative real-time PCR (qRT-PCR) or western blot. The levels of cleaved caspase-12, glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), the markers of cell endoplasmic reticulum stress, were gauged by western blot. Cell viability and apoptosis abilities were evaluated by MTT assay and flow cytometry, respectively. The direct relationship between miR-431-5p and circ_0002945 or TNFAIP1 was verified by the dual-luciferase reporter or RNA immunoprecipitation (RIP) assay.

Results:Our data showed that circ_0002945 was overexpressed in AD serum and amyloid beta (Aβ)_25-35-stimulated SK-N-SH cells and human primary neurons (HPNs). Inhibition of circ_0002945 attenuated Aβ_25-35-induced cell apoptosis and endoplasmic reticulum stress. MiR-431-5p was regulated by circ_0002945 and it was responsible for the circ_0002945 function. Moreover, TNFAIP1 was a miR-431-5p target and circ_0002945 functioned as a ceRNA to control TNFAIP1 expression via miR-431-5p competition. Furthermore, miR-431-5p-mediated suppression of TNFAIP1 ameliorated Aβ_25-35-induced cell apoptosis and endoplasmic reticulum stress.

Conclusion:Our findings establish circ_0002945 as a crucial regulator of Aβ-induced neuron apoptosis and endoplasmic reticulum stress and uncover a novel circ_0002945/miR-431-5p/TNFAIP1 ceRNA network for the Aβ pathogenic pathway in AD.

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