Identification of circRNAs linked to Alzheimer’s disease and related dementias

Abstract

AbstractBackgroundAlthough linear mRNA transcriptome study has been well performed for Alzheimer’s disease (AD), little is known for the non‐coding RNA. Circular RNAs(circRNAs) are particularly notable because of their selective expression in the brain and differential regulation in neurological disease conditions, including AD. CircRNAs are formed from back‐splicing events, and they majorly function as sponges for microRNA and RNA‐binding proteins. Our study examines circRNA expression patterns associated with AD and related dementias in different brain regions.MethodTo detect and quantify cortical circRNAs, we used Mount Sinai Brain Bank (MSBB) rRNA‐depleted RNA sequencing(RNAseq) data derived from inferior frontal gyrus tissue of 278 subjects(216 AD cases, 62 controls) by applying DCC and Circexplor3. To detect hippocampal circRNAs, we generated rRNA‐depleted RNAseq data from 207 human postmortem hippocampal region samples(186 AD, 21 controls) obtained from the BU Alzheimer Disease Research Center. Differentially expressed circRNAs were identified using limma and DESeq2. Both cortical and hippocampal circRNA candidates were further validated using RT‐qPCR in a smaller independent cohort of patients.ResultWe identified over 300 circRNA significantly associated with AD condition (FDR<0.05). Interestingly, a major fraction of these circRNAs are derived from genes involved in excitatory synaptic transmission, axon guidance, and calcium signaling pathways. CircRNA from AD‐linked genes, including APP, PICALM and PSEN1, were identified as top candidates associated with AD in cortex. In the hippocampus, we find circSLC8A1 and circHOMER1 among the top differentially regulated circRNAs. We also find expression of circHOMER1, circMLIP, circATRNL1 among others to be correlated with AD traits of clinical dementia, BRAAK pathology, and amyloid plaque. Our analysis of AD‐only patients and AD patients with vascular or Lewy body dementia revealed differential expression of 39 circRNAs common among all three disease conditions.ConclusionCircRNAs are a novel class of regulatory RNAs but their role in AD pathogenesis is just beginning to be explored. Our study identified circRNA whose expression is linked to AD and are correlated with indices of tauopathy and cognitive loss in cortex and hippocampus. Furthermore, particular circRNAs were differentially expressed among patients with AD or other dementias, suggesting that circRNA might be useful disease biomarkers or targets for disease intervention.