Abstract
Purpose :
Age-related macular degeneration (AMD), Alzheimer's disease (AD) and prion disease (PrD) each represent complex, insidious and progressive pro-inflammatory degeneration of sensing, information integrating and signaling neurons the brain and retina. The purpose of this research was: (i) to accurately determine the expression levels of all 2,700 microRNA (miRNA) and 27,000 messenger RNA (mRNA) species in AMD, AD and PrD; and (ii) to quantify miRNA-mediated pathogenetic signaling involving inflammation, lesion deposition and disruption in the innate-immune system.
Methods :
Human AMD, AD and PrD age- and gender-matched brain and retina; gel-shift assay; micro-fluidic-based GeneChip hybridization, advanced mRNA-miRNA bioinformatics algorithms [including gene set enrichment analysis (GSEA), miRBase, miRTarBase, miRWalk 2.0, Targetscan], LED-Northern dot blot, miRNA and mRNA sequencing, human neuronal-glial (HNG) cells (transplantation grade) in primary culture, RPE cells, brain and retinal tissues from transgenic murine models for AD (TgAD; the 5xFAD model); immunocytochemistry; immunohistochemistry
Results :
For the first time we report the abundance, complexity and speciation of a small family of pathogenic microRNAs: (i) that are all under genetic expression control by the NF-kB (p50/p65) complex; (ii) that include miRNA-34a, miRNA-146a and miRNA-155; (iii) that are all significantly-increased in relative abundance in AMD, AD and PrD; and (iv) next-generation RNA sequencing, feature alignment analysis, miRNA-mRNA complimentarity and bioinformatics analysis further indicate that these 3 miRNAs have a potential to down-regulate about ~1200 target-mRNAs (about 4.4% of the genome) involved in inflammatory aspects and innate-immunity in AMD, AD and PrD.
Conclusions :
Seemingly disparate and unrelated neurosensory and neurological disorders that include AMD, AD and PrD appear to share common microRNA-mediated pathological signaling pathways. Anti-microRNA and anti-NF-kB (p50/p65)-based therapeutic strategies for moderating excessive miRNA-34a-, miRNA-146a- and miRNA-155-based signaling may contribute to an improvement in the pharmacological intervention treatments available for multiple, progressive age-related brain and retinal disorders.
This is a 2020 ARVO Annual Meeting abstract.