Background:
Alzheimer's disease is the most common neurodegenerative disorder. Recent development in sciences has also identified the pivotal role of microRNAs (miRNAs) in AD
pathogenesis.
Objectives:
We proposed a novel method to identify AD pathway-specific statistically significant
miRNAs from the targets of known AD drugs. Moreover, microRNA scaffolds and corresponding
drug scaffolds of different pathways were also discovered.
Material and Methods:
A Wilcoxon signed-rank test was performed to identify pathway-specific
significant miRNAs. We generated feed-forward loop regulations of microRNA-TF-gene-based
networks, studied the minimum free energy structures of pre-microRNA sequences, and clustered
those microRNAs with their corresponding structural motifs of robust transcription factors. Conservation analyses of significant microRNAs were done, and the phylogenetic trees were constructed. We identified 3’UTR binding sites and chromosome locations of these significant microRNAs.
Results:
In this study, hsa-miR-4261, hsa-miR-153-5p, hsa-miR-6766, and hsa-miR-4319 were
identified as key miRNAs for the ACHE pathway and hsa-miR-326, hsa-miR-6133, hsa-miR-4251,
hsa-miR-3148, hsa-miR-10527-5p, hsa-miR-527, and hsa-miR-518a were identified as regulatory
miRNAs for the NMDA pathway. These miRNAs were regulated by several AD-specific TFs,
namely RAD21, FOXA1, and ESR1. It has been observed that anisole and adamantane are important chemical scaffolds to regulate these significant miRNAs.
Conclusion:
This is the first study that developed a detailed correlation between known AD drug
scaffolds and their AD target-specific miRNA scaffolds. This study identified chromosomal locations of microRNAs and corresponding structural scaffolds of transcription factors that may be responsible for miRNA co-regulation for Alzheimer's disease. Our study provides hope for therapeutic improvements in the existing microRNAs by regulating pathways and targets.