CircRNA-ceRNA Network Revealing the Potential Regulatory Roles of CircRNA in Alzheimer’s Disease Involved the cGMP-PKG Signal Pathway

Abstract

Background: Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. The characteristic pathologies include extracellular senile plaques formed by β-amyloid protein deposition, neurofibrillary tangles formed by hyperphosphorylation of tau protein, and neuronal loss with glial cell hyperplasia. Circular RNAs (circRNAs) are rich in miRNA-binding sites (miRNA response elements, MREs), which serve as miRNA sponges or competitive endogenous RNAs (ceRNAs). Although several research groups have identified dysregulated circRNAs in the cerebral cortex of SAMP8 mice or APP/PS1 mice using deep RNA-seq analysis, we need to further explore circRNA expression patterns, targets, functions and the signaling pathways involved in the pathogenesis of AD and in particular the hippocampal circRNA expression profiles in AD.Methods: We used deep RNA sequencing to investigate circRNA-ceRNA network patterns in the hippocampus of APP/PS1 mice.Results: In our study, 70 dysregulated circRNAs, 39 dysregulated miRNAs and 121 dysregulated mRNAs were identified between the APP/PS1 group and the wild-type group at 8 months in the hippocampus of the mice. Through correlation analysis, we identified 11 dysregulated circRNAs, 7 dysregulated miRNAs and 8 dysregulated mRNAs forming 16 relationships in the circRNA-miRNA-mRNA regulatory network. Gene ontology (GO) analysis indicated that the dysregulated circRNAs were most enriched in biological metabolic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the dysregulation of circRNAs was enriched in the cGMP-PKG signaling pathway, cAMP signaling pathway, Hippo signaling pathway, platelet activation, long-term potentiation and axon guidance. In addition, our findings preliminarily verified that the novel_circ_0003012/mmu-miR-298-3p/Smoc2 signaling axis may regulate the pathophysiology of AD by affecting the cGMP-PKG signaling pathway.Conclusions: These newly identified circRNAs in networks and signaling pathways reveal potential diagnostic or therapeutic targets for AD.

Genetic Polymorphisms Associated with Prothrombin Time and Activated Partial Thromboplastin Time in Chinese Healthy Population

“…Primary hemostasis and arterial thrombosis include platelet activation and aggregation to generate thrombi, and these processes are controlled by intracellular signaling networks [ 60 ]. The cGMP/PKG pathway mediates the suppression of platelet aggregation, according to numerous studies [ 61 , 62 , 63 ].…”

Exosomal MicroRNAs modulate the cognitive function in fasudil treated APPswe/PSEN1dE9 transgenic (APP/PS1) mice model of Alzheimer's disease

“…cGMP-PKG signaling pathway in the hippocampus of AD mice has been shown to dysregulates circRNAs 47,48 . mmu-miR-298-3p/Smoc2 signaling axis may regulate the pathophysiology of AD by affecting the cGMP-PKG signaling pathway 49 .…”

Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy

“…MREs were known as the guide strand, retained within miRNA-induced silencing complex (miRISC), targeted to mRNA with partially complementary sequences (3,4).ceRNAs serve as endogenous sponges,the competitive inhibitors of miRNA function, showing another novel layer of posttranscriptional regulation (1,5). Recently, many researchers have focused on the ceRNA interactions which uncover a novel mechanism and play important roles in differentiation (2,6,7), cancer (8)(9)(10)(11), immunerelated diseases (12), cardiovascular diseases (13,14), neurological diseases (15,16), etc. Linc-MD1 "sponges" miR-133 and miR-135 to regulate the expression of transcription factors MAML1 and MEF2C, then to governs the time of muscle differentiation in mouse and human myoblasts (2).The lncRNA H19 functions as a ceRNA to sponge miRNA let-7 family leading to an increase in expression of let-7 targets in breast cancer,ovarian cancer and pancreatic cancer (8).Notably, ceRNA also acts crucial role in reproductive health (17), such as fetal and organ development (18), spontaneous abortion (19)(20)(21) and eclampsia in pregnancy (22).…”