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

Abstract

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).

N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease

“…Some previous studies have reported dysregulation of circRNAs in pre-symptomatic AD, including downregulated circHOMER1, which is negatively linked with the Clinical Dementia Rating and Braak score in AD patients [ 5 ]. Other studies have characterized the circRNA-miRNA ceRNA networks and identified variations in circRNA expression between brain regions in AD and related dementias [ 8 , 9 ]. Additionally, Trinchese et al [ 17 ] summarized age-related progression in APP/PS1 mice, and observed that both long-term potentiation and short-term memory are impaired in 3-month-old APP/PS1 mice, and become worsened as the mice are getting older, indicating that synaptic impairments occur at an early stage before obvious Aβ deposits are formed.…”

“…Aberrant expression of circRNAs occurs in the early stage of AD, and is significantly correlated with AD diagnosis, neuropathological severity, and clinical dementia severity [ 5 ]. The circRNA expression pattern and the circRNA/miRNA competing endogenous RNA (ceRNA) network have been extensively investigated in both AD patients and animal models across different brain regions and stages [ 5 , 8 – 10 ]. Certain circRNAs play essential roles in regulating Aβ deposition, tau phosphorylation, and neuroinflammation [ 11 – 14 ].…”

Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease

“…This reduction in miR-137 availability could result in the increased expression of target genes. However, our in silico analysis did not confirm this observation [ 34 ]. Our study reported that out of the eight miRNAs potentially interacting with circPSEN1, mir-4668-5p and mir-5584-5p are the only ones that exhibit exclusivity to circPSEN1 and do not engage with PSEN1 mRNA.…”

“…Moreover, mutations in the PSEN1 gene contribute to the aggregation of Aβ42 in the brains of AD patients [ 33 ]. Following an extensive literature review and a thorough assessment of circular RNA-seq data obtained from human AD samples, we found that only two studies have reported the upregulation of PSEN1-derived circRNAs in individuals diagnosed with AD [ 16 , 34 ]. In the leading project, the discriminatory potential of circPSEN1 counts was assessed in differentiating individuals with autosomal dominant AD (ADAD) from those with sporadic AD and healthy controls.…”

CircRNAs in Alzheimer's disease: What are the prospects?

“…Therefore, the identification of reliable and effective biomarkers for the early stages of AD is a strategic imperative. CircRNAs that exist in serum, plasma, and cerebrospinal fluid (CSF) present themselves as strong candidates for use as diagnostic biomarkers, given their ease of identification through simple detection methods and their remarkable stability during storage and handling [ 88 ]. Future research should prioritize the use of highly sensitive RNA analysis methods to validate the utility of specific circRNAs as preclinical or clinical diagnostic biomarkers for AD.…”