IntroductionCircular RNAs (circRNAs) exhibit selective expression in the brain and differential regulation in Alzheimer's disease (AD). To explore the role of circRNAs in AD, we investigated how circRNA expression varies between brain regions and with AD‐related stress in human neuronal precursor cells (NPCs).MethodsRibosomal RNA–depleted hippocampus RNA‐sequencing data were generated. Differentially regulated circRNAs in AD and related dementias were detected using CIRCexplorer3 and limma. circRNA results were validated using quantitative real‐time PCR of cDNA from the brain and NPCs.ResultsWe identified 48 circRNAs that were significantly associated with AD. We observed that circRNA expression differed by dementia subtype. Using NPCs, we demonstrated that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in the AD brain.DiscussionOur study shows that differential expression of circRNA can vary by dementia subtype and brain region. We also demonstrated that circRNAs can be regulated by AD‐linked neuronal stress independently from their cognate linear messenger RNAs (mRNAs).

We conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in the human hippocampus and cortex brain regions. We validated prior studies of circRNA in the AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.

BackgroundAlthough 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.