Small RNAs, short but mighty: the unknown players in AD pathobiology

Abstract

AbstractBackgroundMicroRNAs (miRNAs) are known to be involved in Alzheimer’s disease (AD), but little is known about the other classes of small RNAs (sRNAs). We performed the first high throughput, unbiased study of sRNAs in AD brains aiming to build regulatory networks involved in AD pathogenesis.MethodSampling included 244 parietal brain samples from the Knight‐ADRC, 93% of which were AD cases, 90% male, and with a mean age of 83. After RNA extraction with a Maxwell RSC instrument, we generated sRNA libraries using the RealSeq®‐AC sRNA kit version 2. Libraries were aligned to the reference genome and known small RNAs using Bowtie2. After stringent quality control we performed differential expression analyses using DESeq2, adjusting by age, sex, post‐mortem interval and methodological variables. Finally, we integrated the sRNA data with RNA‐seq data from the same samples to identify correlations with known AD genes.ResultWe identified four miRNAs and fifty‐six Piwi‐interacting RNAs (piRNAs) and one snoRNA that are significantly dysregulated in AD brains. We observed no significantly dysregulated tRNAs, suggesting that translational machinery was intact. We found significant positive correlation between miR‐6126 and miR‐3614‐3p, miR‐6126 and two piRNAs, as well as relationships among several piRNAs. Further, we identified dysregulated sRNAs that significantly correlate with AD genes such as APP, PSEN1, and PSEN2. For example, piR‐3746502 negatively correlates to over ten AD‐genes but associates with MS4A4A and TREM2 in the opposite direction of other AD genes, consistent with biological knowledge.ConclusionOur findings emphasize the importance of non‐coding RNAs in the pathobiology of AD. We showed that sRNAs beyond miRNAs contribute to AD and that large‐scale studies of sRNAs in brain are crucial to understand the regulation of the pathways involved in AD pathogenesis. Here, we described that several sRNAs involved in the regulation of known AD genes, with associations in the expected direction.