MicroRNAs targeting Nicastrin regulate Aβ production and are affected by target site polymorphisms

摘要: Despite the growing number of genome-wide association studies, involvement polymorphisms in microRNA target sites (polymiRTS) Alzheimer’s disease (AD) remains poorly investigated. Recently, we have shown that AD-associated single nucleotide (SNPs) present 3’untranslated region (3’UTR) Amyloid precursor protein (APP) could directly affect miRNA function. In theory, loss (miRNA) function lead to risk for AD by increasing APP expression and Aβ peptide production. this study, tested hypothesis Nicastrin, a γ-secretase subunit involved generation, be regulated miRNAs, consequently affected 3’UTR polymorphisms. Bioinformatic analysis identified 22 putative bindings located or near Nicastrin 3'UTR From these candidates, six were previously expressed human brain. We miR-24, miR-186 miR-455 as regulators expression, both vitro under physiological conditions cells, which resulted altered secretion. Using luciferase-based assays, further demonstrated rs113810300 rs141849450 SNPs miRNA-mediated repression Nicastrin. Notably, completely abolished miR-455-mediated Finally, variant was 1 out 511 cases, but not 631 controls. These observations set stage future studies exploring role miRNAs AD.