Soluble Beta-Amyloid Peptides, but Not Insoluble Fibrils, Have Specific Effect on Neuronal MicroRNA Expression

Recent studies indicate that soluble beta-amyloid (sA beta) oligomers, rather than their fibrillar aggregates, contribute to the pathogenesis of Alzheimer's disease (AD), though the mechanisms of their neurotoxicity are still elusive. Here, we demonstrate that sA beta derived from 7PA2 cells exert a much stronger effect on the regulation of a set of functionally validated microRNAs (miRNAs) in primary cultured neurons than the synthetic insoluble A beta fibrils (fA beta). Synthetic sA beta peptides at a higher concentration present comparable effect on these miRNAs in our neuronal model. Further, the sA beta-induced miR-134, miR-145 and miR-210 expressions are fully reversed by two selective N-methyl-d-aspartate (NMDA) receptor inhibitors, but are neither reversed by insulin nor by forskolin, suggesting an NMDA receptor-dependent, rather than PI3K/AKT or PKA/CREB signaling dependent regulatory mechanism. In addition, the repression of miR-107 expression by the sA beta containing 7PA2 CM is likely involved multiple mechanisms and multiple players including NMDA receptor, N-terminally truncated A beta and reactive oxygen species (ROS).