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

Recent studies indicate that soluble β-amyloid (sAβ) 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 sAβ 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 Aβ fibrils (fAβ). Synthetic sAβ peptides at a higher concentration present comparable effect on these miRNAs in our neuronal model. Further, the sAβ-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 sAβ containing 7PA2 CM is likely involved multiple mechanisms and multiple players including NMDA receptor, N-terminally truncated Aβ and reactive oxygen species (ROS).

近年研究表明，可溶性β淀粉样蛋白（soluble β-amyloid, sAβ）寡聚体而非其纤维状聚集体，参与阿尔茨海默病（Alzheimer's disease, AD）的发病进程，但其神经毒性的具体机制仍未阐明。本研究显示，相较于合成不溶性Aβ纤维（fAβ），源自7PA2细胞的sAβ对原代培养神经元中一系列经功能验证的微小RNA（microRNAs, miRNAs）的调控作用更为显著。在本神经元模型中，高浓度的合成sAβ多肽对这些微小RNA的调控效果与之相当。进一步研究发现，两种选择性N-甲基-D-天冬氨酸（N-methyl-d-aspartate, NMDA）受体抑制剂可完全逆转sAβ诱导的miR-134、miR-145及miR-210表达上调，而胰岛素与佛司可林均无此逆转效果，提示该调控机制依赖NMDA受体，而非PI3K/AKT或PKA/CREB信号通路。此外，含sAβ的7PA2条件培养基对miR-107表达的抑制作用，可能涉及多种机制与多种调控因子，包括NMDA受体、N端截短型Aβ以及活性氧（reactive oxygen species, ROS）。