Network Analysis to Identify MicroRNAs Involved in Alzheimer's Disease and to Improve Drug Prioritization

Background: Advances in the understanding of molecular mechanisms of human diseases, along with the generation of large amounts of molecular datasets, have highlighted the variability between patients and the need to tailor therapies to individual characteristics. In particular, RNA-based therapies hold strong promise for new drug development, as they can be easily designed to target specific molecules. Gene and protein functions, however, operate within a highly interconnected network, and inhibiting a single function or repressing a single gene may lead to unexpected secondary effects. In this study, we focused on genes associated with Alzheimer’s disease, a progressive neurodegenerative disorder characterized by complex pathological processes leading to cognitive decline and dementia. Its hallmark features include the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Methods: We built a protein interaction network subgraph seeded on five Alzheimer’s-associated genes, including tau and amyloid-β precursor, and integrated it with microRNAs in order to select regulated nodes, study the effects of their depletion on signaling pathways, and prioritize targets for microRNA-based therapeutic approaches. Results: We identified nine protein nodes as potential candidates (Pik3R1, Bace1, Traf6, Gsk3b, Akt1, Cdk2, Adam10, Mapk3 and Apoe) and performed in silico node depletion to simulate the effects of microRNA regulation. Conclusions: Despite intrinsic limitations of the approach, such as the incompleteness of the available information or possible false associations, the present work shows clear potential for drug design and target prioritization and underscores the need for reliable and comprehensive maps of interactions and pathways.