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. 2022 Oct 31;23(21):13232.
doi: 10.3390/ijms232113232.

A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer's Disease and Mild Cognitive Impairment from Healthy Controls

Paola Piscopo  1 , Valeria Manzini  1   2 , Roberto Rivabene  1 , Alessio Crestini  1 , Loredana Le Pera  3 , Elisabetta Pizzi  3 , Caterina Veroni  1 , Giuseppina Talarico  4 , Martina Peconi  4 , Anna Elisa Castellano  5 , Carmelo D'Alessio  5 , Giuseppe Bruno  4 , Massimo Corbo  6 , Nicola Vanacore  7 , Eleonora Lacorte  7
Affiliations

A Plasma Circular RNA Profile Differentiates Subjects with Alzheimer's Disease and Mild Cognitive Impairment from Healthy Controls

Paola Piscopo et al. Int J Mol Sci. .

Abstract

The most frequently used biomarkers to support the diagnosis of Alzheimer’s Disease (AD) are Aβ42, total-Tau, and phospho-tau protein levels in CSF. Moreover, magnetic resonance imaging is used to assess hippocampal atrophy, 18F-FDG PET to identify abnormal brain metabolism, and PET imaging for amyloid deposition. These tests are rather complex and invasive and not easily applicable to clinical practice. Circulating non-coding RNAs, which are inherently stable and easy to manage, have been reported as promising biomarkers for central nervous system conditions. Recently, circular RNAs (circRNAs) as a novel class of ncRNAs have gained attention. We carried out a pilot study on five participants with AD and five healthy controls (HC) investigating circRNAs by Arraystar Human Circular RNA Microarray V2.0. Among them, 26 circRNAs were differentially expressed (FC ≥ 1.5, p < 0.05) in participants with AD compared to HC. From a top 10 of differentially expressed circRNAs, a validation study was carried out on four up-regulated (hsa_circRNA_050263, hsa_circRNA_403959, hsa_circRNA_003022, hsa_circRNA_100837) and two down-regulated (hsa_circRNA_102049, hsa_circRNA_102619) circRNAs in a larger population. Moreover, five subjects with mild cognitive impairment (MCI) were investigated. The analysis confirmed the upregulation of hsa_circRNA_050263, hsa_circRNA_403959, and hsa_circRNA_003022 both in subjects with AD and in MCI compared to HCs. We also investigated all microRNAs potentially interacting with the studied circRNAs. The GO enrichment analysis shows they are involved in the development of the nervous system, and in the cellular response to nerve growth factor stimuli, protein phosphorylation, apoptotic processes, and inflammation pathways, all of which are processes related to the pathology of AD.

Keywords: AD; Alzheimer Disease; MCI; biomarkers; circRNA; circular RNA; microarray Real-Time PCR; mild cognitive impairment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Graphic representation and Scatter plots of circRNAs levels between AD patients and HCs. * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 2
Figure 2
Graphic representation of circRNA expression levels in males and females in subjects with HC and AD. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.
Figure 3
Figure 3
Graphic representation of circRNA expression levels in HC, AD, and MCI subjects. * p < 0.05, ** p < 0.01, *** p < 0.001.
Figure 4
Figure 4
Receiver operating characteristic (ROC) curve of differentially expressed circRNAs in AD vs HC. AUC: Area Under the Curve.
Figure 5
Figure 5
circRNA-miRNA network was reconstructed by Cytoscape 3.9.0. Red dots represent hasa_circRNAs, whilst hsa_miRNAs are shown as grey dots. Hsa_miRNAs functioning as bridges between hsa_circ_RNAs clusters are labeled.
Figure 6
Figure 6
Comparison of Biological Processes GO terms over-represented in the groups of target proteins of each differentially expressed circRNA. All terms statistically enriched in at least one of the four groups (circRNA_003022, circRNA_102619, circRNA_102049, circRNA_050263) are reported in the heatmaps, with adjusted p-values plotted in blue-grey scale color, where blue indicates higher significant results.
Figure 7
Figure 7
Comparison of KEGG and Reactome pathways (on the top) and tissues (on the bottom) significantly over-represented in the annotations of groups of target proteins of each differentially expressed circRNA. All terms statistically enriched in at least one of the four groups (circRNA_003022, circRNA_102619, circRNA_102049, circRNA_050263) are reported in the heatmaps, with adjusted p-values plotted in red- and green-grey color scales, respectively.
Figure 7
Figure 7
Comparison of KEGG and Reactome pathways (on the top) and tissues (on the bottom) significantly over-represented in the annotations of groups of target proteins of each differentially expressed circRNA. All terms statistically enriched in at least one of the four groups (circRNA_003022, circRNA_102619, circRNA_102049, circRNA_050263) are reported in the heatmaps, with adjusted p-values plotted in red- and green-grey color scales, respectively.
Figure 8
Figure 8
Network of circRNA-miRNA-mRNA for selected targets. CircRNAs are represented as red hexagons, miRNAs as grey dots, and mRNAs as green squares.
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