Department of Computer Science, Virginia Commonwealth University, Richmond, VA, 23284, USA.
Department of Chemistry & Biochemistry, University of Southern Mississippi, Hattiesburg, MS, 39406, USA.
Sci Rep. 2017 Sep 4;7(1):10370. doi: 10.1038/s41598-017-09794-x.
Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aβ homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aβ and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aβ dynamics distinctively in three broadly-defined FA concentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aβ, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aβ aggregation pathways.
淀粉样蛋白 β (Aβ) 肽的聚集是支撑阿尔茨海默病 (AD) 病理学的重要事件。Aβ 聚集物，特别是低分子量寡聚物，是 AD 中的主要毒性物质，因此，人们越来越有兴趣了解其形成和行为。聚集是一个依赖于成核的过程，其中预成核事件主要由 Aβ 同型相互作用主导。预成核过程中的动态通量和随机性使得反应容易受到其他分子的干扰。在这种情况下，我们通过两种独立的工具集，即简化模型 (ROM) 和集合动力学模拟 (EKS)，研究了 Aβ 与脂肪酸 (FA) 之间的异型相互作用。我们观察到，FA 在三个广泛定义的 FA 浓度范围内对 Aβ 动力学产生显著影响，这三个浓度范围分别含有非胶束、拟胶束或胶束相。虽然非胶束相促进了成纤维途径的纤维形成，但拟胶束相和胶束相主要促进了成纤维途径以外的寡聚物形成，尽管通过微妙不同的机制。重要的是，成纤维途径以外的寡聚物在有限的分子尺寸内饱和，并且可能具有与沿着成纤维途径形成的寡聚物不同的整体构象，这表明 Aβ 产生了不同的构象菌株，这可能具有深远的表型后果。我们的结果验证了先前的实验观察结果，并提供了对生物界面在调节 Aβ 聚集途径方面的潜在影响的深入了解。
