NEW YORK – By tallying the transcripts in postmortem brain samples from individuals with or without Alzheimer's disease (AD), an Indiana University- and Texas A&M University-led team has uncovered noncoding RNA (ncRNA) expression patterns and posttranscriptional modifications (PTMs) with apparent ties to AD — features that were further linked to related gene regulatory networks.
"Our study aims to provide a valuable resource for the broader research community studying AD," senior and corresponding author Leng Han, a biostatistics and health data science researcher affiliated with Indiana University and Texas A&M University, and colleagues wrote in Science Advances on Friday.
For their study, the investigators analyzed RNA sequencing data generated on 915 postmortem brain samples collected by the Mount Sinai/JJ Peters V Medical Center Brain Bank Study (MSBB) and 545 postmortem samples from the Mayo Clinic Alzheimer's Disease Genetics study, which together spanned half a dozen brain regions: the anterior prefrontal cortex, superior temporal gyrus, parahippocampal gyrus, inferior frontal gyrus, temporal cortex, and cerebellum.
Using these data, the team searched for AD-associated long noncoding RNAs (lncRNAs) and enhancer RNAs (eRNAs), along with adenosine-to-inosine RNA editing events and a form of posttranscriptional modification (PTM) known as alternative polyadenylation (APA).
"Our study aims to establish a comprehensive data platform for ncRNAs and PTMs in AD to advance related research," the authors explained, noting that the current findings "suggest critical roles of ncRNAs and PTMs in AD."
Based on expression profiles for more than 33,300 lncRNAs and nearly 92,900 eRNAs, together with 900,221 adenosine-to-inosine RNA editing events and 53,763 APA modification events, the researchers flagged ncRNAs and PTMs associated with AD within or across the brain regions considered.
The team's analyses led to 25,351 ncRNAs with altered expression linked to AD traits, for example, including 933 lncRNAs with differential expression in the AD brain samples and 23 differentially expressed eRNAs with apparent ties to AD traits such as clinical dementia or neuritic plaque scores.
Along with follow-up analyses focused on differentially expressed ncRNAs and altered PTM events within specific brain regions, the AD-related transcriptional shifts provided fodder for the investigators' gene set enrichment and regulatory network analyses.
"Our study presented the landscape of ncRNA and PTM large-scale samples and revealed numerous instances of alterations that may be associated with AD," the authors explained, noting that they have gone on to establish a "user-friendly data portal" known as ADatlas to "explore, visualize, and browse these data."
Nevertheless, the authors cautioned that "predominant European ancestry in both cohorts poses a limitation to the generalizability and applicability of the studies," and called for further transcriptomics-based analyses on brain samples from additional individuals with or without AD.
"In the future, we will integrate datasets to characterize ncRNAs and [posttranscriptional modification] along with more large-scale AD cohort releases," the authors suggested, "which would continue to benefit [the] research community in investigating the functions and mechanisms of ncRNAs and [posttranscriptional modification] in AD."