Progressive dysregulation of circular RNAs in the hippocampus of a transgenic mouse model of amyloidosis

Abstract

AbstractBackgroundCircular RNAs (circRNAs) are a class of RNAs that act as transcriptional regulators. They have a circular structure and are produced from back‐splicing events, which makes them more stable than linear RNAs. In Alzheimer’s disease (AD), the role of circRNAs remains elusive. Here, we aimed to evaluate whether the transcription of circRNAs is altered in the hippocampus, a region highly vulnerable to AD, of a transgenic amyloid mouse model.MethodWe selected hippocampal RNA‐sequencing or microarray datasets of circRNAs of the APPswe/PSEN1dE9, a widely used transgenic amyloid mouse model, from the NCBI databases. CircRNAs were detected with the CIRI2 algorithm by using the gene symbol of the parent transcript and the transcript ID. We identified the differently expressed circRNAs between APPswe/PSEN1dE9 and age‐matched wild‐types using the DESeq2 method (p‐value < 0.01). The packages UpSetR and VennDiagram were used to uncover the circRNAs commonly altered between the studies. All analyses were performed in R.ResultFrom 12 databases, three had hippocampal circRNA data of 4, 6, and 8‐month‐old APPswe/PSEN1dE9 mice (GSE166393; GSE158995; and PRJNA712946, n = 3 per group). Amyloid‐beta (Aβ) starts to deposit at six months in the APPswe/PSEN1dE9 hippocampus. The number of dysregulated circRNAs increased with age: 41 (4‐month‐old), 82 (6‐month‐old), and 425 (8‐month‐old) (Figure 1). Interestingly, only one circRNA was shared between the three studies at all time points, originating from the CCDC141 gene. Additionally, 15 circRNAs were shared in at least two ages, such as CD2AP, FMN1, HOMER1, IL1RAP, NDST3, and TET1 (Please, see the full list of intersections in Figure 2). By dividing groups into pre‐plaque (4‐month‐old) and amyloid (6 and 8‐month‐old) phases, we found that four altered circRNAs were shared in both stages, 37 exclusively in pre‐amyloid stage and 490 in amyloid stage (Figure 3).ConclusionOur results demonstrate an increasing dysregulation in circRNAs profiles in the hippocampus of the APP/PS1 mice. Considering the role of circRNAs as transcriptional regulators, one could argue that these progressive changes may impact gene expression in AD‐related brain regions.