. An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations. Nat Neurosci. 2019 Nov;22(11):1903-1912. Epub 2019 Oct 7 PubMed.


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  1. In this manuscript, “An atlas of cortical circular RNA expression demonstrates clinical and pathological associations with Alzheimer disease,” Dube et al. evaluated parietal RNA-Seq data from 13 control and 83 AD samples from Washington University and an independent AD RNA-Seq data from a Mount Sinai Brain Bank data set of 195 individuals and four cortical regions (inferior frontal gyrus, frontal pole, superior temporal gyrus, parahippocampal gyrus) to quantify circular RNA (circRNA) expression. They evaluated 3,547 circRNAs in the discovery and 3,924 circRNAs in the replication cohort. The authors performed associations between brain circRNA levels, AD status, neuropathology (Braak scores) and clinical impairment (clinical dementia rating scale).

    They identified 37 circRNAs that associated with at least one of these outcomes in the discovery cohort. Meta-analysis of the findings after inclusion of the replication cohort using the inferior frontal gyrus data revealed 164 circRNAs that associated with one of the AD traits and survived Bonferroni correction. Three circRNAs were consistently associated with all AD traits across all meta-analysis involving all four cortical regions of the replication cohort; and 11 such circRNAs associated with at least two of the traits, suggesting replicability of this subset across brain regions. The authors evaluated associations in a small subset of individuals (12 AD versus 53 controls) with pathologic evidence of AD but clinical evidence of at most mild dementia (CDR≤0.5) and found consistencies with those from the WashU and Mount Sinai cohorts, including those with CDR>0.5 (214 AD). This is not surprising since the underlying neuropathology in both subsets is AD neuropathology regardless of the clinical severity observed.

    Investigation of RNA-Seq data from 21 autosomal-dominant AD parietal cortex samples revealed 59 circRNAs that were differentially expressed even after correcting for Braak stage in both this and the discovery data sets, where the effect sizes were greater in the former. The top 10 circRNAs were found to explain more of the proportion of variation in the traits assessed than APOE4 or estimated neuronal proportions. Two of the AD-associated circRNAs (circCORO1C and circHOMER1) reside in co-expression networks that also include some AD risk genes. The authors also identified putative miRNA binding sites for microRNAs within circRNAs.

    This study adds to the growing body of literature which highlights gene expression differences between the brains of AD patients versus controls or those with other neurodegenerative diseases (Allen et al., 2018; Zhang et al., 2013; McKenzie et al., 2017; Raj et al., 2018). These studies identified differentially expressed genes and networks that are implicated in biological processes, including innate immunity and myelination. Some of these networks were also found to be enriched for genes that harbor risk variants for AD. Collectively, these studies pinpoint biological pathways and key molecules in these pathways that may drive AD and therefore be potential therapeutic targets.

    An important potential caveat in studies that utilize autopsy tissue is the inability to discern cause versus effect, as the detected changes in the transcriptome and proteome (Seyfried et al., 2017) could be a consequence, rather than a cause of the neuropathology. Cellular proportion changes secondary to the disease process can also account for the detected differential expression. Some studies address this concern by adjusting for cellular proportions using surrogate markers (Allen et al., 2018) and/or incorporating data from brain regions that are essentially unaffected by the gross disease pathology (Allen et al., 2018; Allen et al., 2018). The study by Dube et al. indicates their adjustment for cell proportion changes, which partially alleviates this concern. It will be important to determine in future studies whether these findings replicate in brain regions that are devoid of neuropathology, which will support their potential causality in the disease process.

    The findings also need validation through both microRNA and protein studies from the same brain samples to determine whether circRNAs indeed influence microRNA levels and whether these effects are translated into changes in protein levels in the brain. Integration of genomic data will help determine whether genetic variation accounts for any of the observed cirRNA changes and whether such genetic variants also account for AD risk, which will garner support for an AD causal effect for this mechanism.

    Finally, this study is another example of the significant utility of the multi-omics data generated and shared by the Accelerating Medicines Partnership-Alzheimer’s Disease (AMP-AD) community (Allen et al., 2016; Wang et al., 2018; Ping et al., 2018; St John-Williams et al., 2017; De Jager et al., 2018). Dube et al. utilized the brain transcriptome data generated and shared by the AMP-AD Mount Sinai team. The available data from AMP-AD should enable replication of these findings in additional and larger data sets.


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    View all comments by Nilufer Ertekin-Taner
  2. Although the biogenesis of Aβ in familial AD is well-documented, Aβ production in sporadic AD is not well understood. We identified circAβ-a and analyzed its formation in prefrontal cortex samples of sporadic AD patients, non-dementia controls, and transient transfection assays.

    According to circbase, circAβ-a (hsa_circ_0007556) can be found in various human brain tissues (diencephalon, cerebellum, occipital lobe, frontal cortex, parietal lobe, temporal lobe). We also identified 16 additional circAβ forms both in frontal lobe and hippocampus. With the aid of intron-mediated enhancement, we confirmed that circAβ-a served as a template for the biosynthesis of an Aβ-related protein (Aβ175) in HEK293 cells.

    In addition, the unique C-terminal peptide of Aβ175 was identified in human brain samples. Furthermore, Aβ175 was processed into Aβ peptides, representing a novel route of Aβ generation that might give rise to new perspectives on the molecular mechanisms leading to the manifestation of Alzheimer’s disease.

    Recently, circRNA expression and its correlation to AD pathology was investigated. With extensive RNA-sequencing of AD brain samples, Dube et al. report that 10 circRNAs have strong pathological associations with AD. Quite surprisingly, circAβ-a and its other isoforms were not included. This could be due to insufficient depth of sequencing with respect to circAβ isoforms as a result of bias in library construction.

    Furthermore, the involvement of circAβ variants in AD pathology may lie in their translation activation, rather than changes in their circRNA levels. Interestingly, the mouse ortholog of circRTN4, one of the circRNAs with strong correlation to AD, has been previously reported to produce proteins (both monomer and repeating multimers by rolling cycle translation). Meanwhile, RTN4 protein (NogoA) is known to play a role in AD through BACE1 activity regulation. Thus, circRTN4-derived polypeptides may have a regulatory role in AD akin to its NogoA protein counterpart.

    Additional polypeptide-producing circRNAs with strong AD association could possibly play a role. In any event, the investigation of biological roles of circAβ-a offers new perspectives in the search for underlying mechanisms of sporadic Alzheimer’s disease, which could ultimately lead to the design of disease-modifying drugs.


    . Circular RNA Encoded Amyloid Beta peptides-A Novel Putative Player in Alzheimer's Disease. Cells. 2020 Sep 29;9(10) PubMed.

    . A universal approach to investigate circRNA protein coding function. Sci Rep. 2019 Aug 12;9(1):11684. PubMed.

    . Role of circular RNAs in brain development and CNS diseases. Prog Neurobiol. 2020 Mar;186:101746. Epub 2020 Jan 10 PubMed.

    View all comments by Dingding Mo

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  1. Mysterious RNA Circles Crop up in Alzheimer’s Brain