Department, of Chemical Engineering, Arizona State University, Tempe, AZ 85287, USA.
Biotechnol Prog. 2010 Jul-Aug;26(4):1172-9. doi: 10.1002/btpr.396.
Although Alzheimer's disease (AD) is characterized by the extracellular deposition of fibrillar aggregates of beta-amyloid (Abeta), transient oligomeric species of Abeta are increasingly implicated in the pathogenesis of AD. Natively unfolded monomeric Abeta can misfold and progressively assemble into fibrillar aggregates, following a well-established "on pathway" seeded-nucleation mechanism. Here, we show that three simple saccharides, mannose, sucrose, and raffinose, alter Abeta aggregation kinetics and morphology. The saccharides inhibit formation of Abeta fibrils but promote formation of various oligomeric aggregate species through different "off pathway" aggregation mechanisms at 37 degrees C but not at 60 degrees C. The various oligomeric Abeta aggregates formed when coincubated with the different saccharides are morphologically distinct but all are toxic toward SH-SY5Y human neuroblastoma cells, increasing the level of toxicity and greatly prolonging toxicity compared with Abeta alone. As a wide variety of anti-Abeta aggregation strategies are being actively pursued as potential therapeutics for AD, these studies suggest that care must be taken to ensure that the therapeutic agents also block toxic oligomeric Abeta assembly as well as inhibit fibril formation.
尽管阿尔茨海默病（AD）的特征是β-淀粉样蛋白（Abeta）的纤维状聚集物的细胞外沉积，但 Abeta 的瞬态寡聚体越来越多地与 AD 的发病机制有关。天然无规的单体 Abeta 可以错误折叠并逐渐组装成纤维状聚集物，遵循一种成熟的“成核途径”种子化机制。在这里，我们表明三种简单的糖，甘露糖、蔗糖和棉子糖，改变了 Abeta 聚集的动力学和形态。这些糖在 37°C 下通过不同的“非成核途径”聚集机制抑制 Abeta 纤维的形成，但不抑制 60°C 下 Abeta 纤维的形成。当与不同的糖共同孵育时，形成的各种寡聚 Abeta 聚集体在形态上是不同的，但都对 SH-SY5Y 人神经母细胞瘤细胞有毒性，与单独的 Abeta 相比，增加了毒性水平，并大大延长了毒性持续时间。由于各种抗 Abeta 聚集的策略都被积极地作为 AD 的潜在治疗方法进行研究，这些研究表明，必须注意确保治疗剂既能阻断有毒的寡聚 Abeta 组装，又能抑制纤维形成。
