Assessing circular RNAs in Alzheimer disease

Abstract

AbstractCircular RNAs (circRNA) are evolutionary conserved non-coding RNAs resulting from the backsplicing of precursor messengers. Recently, a circular-transcriptome-wide study of circRNA in brain tissue from patients with Alzheimer’s disease (AD) has revealed a striking association between the expression of circRNA and AD pathological diagnosis. In the present study, we aimed at replicating the major findings in an independent case series comprising definitive sporadic and familial AD. In order to assess the specificity of circRNA changes, we also included cases with frontotemporal lobar degeneration (FTLD), comprising brain specimens with TDP-43 aggregates (FTLD-TDP43) and samples that presented Tau accumulation (FTLD-Tau). Through a quantitative PCR approach, we evaluated a total of eight circRNAs that surpassed the significant threshold in the former meta-analysis (circHOMER1, circDOCK1, circKCNN2, circMAN2A1, circFMN1, circRTN4, circMAP7, and circPICALM). Average expression changes between AD patients and controls followed the same directions as previously reported, suggesting an overall upregulation of circDOCK1, circMAP7, circMAN2A1, circRTN4 and circPICALM, and a downregulation of the remainder (circHOMER1, circFMN1 and circKCNN2) in AD brain tissue. We also confirmed an exacerbated alteration in circRNA expression in the Mendelian AD group compared to the sporadic forms. Two circRNAs, circHOMER1 and circKCNN2, also showed significant expression alterations in the group of FTLD-Tau and FTLD-TDP43, respectively. Overall, these results reinforce the conception that expression of circRNAs is altered in Alzheimer’s disease, and also suggest a wider involvement of this particular class of RNA in other neurodegenerative dementias.