Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Chemistry, Biophysics Program, Biomedical Engineering, Macromolecular Engineering and Science, and Michigan Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
J Phys Chem Lett. 2022 Oct 13;13(40):9303-9308. doi: 10.1021/acs.jpclett.2c02362. Epub 2022 Sep 29.
A recently proposed lipid-chaperone hypothesis suggests that free lipid molecules, not bound to membranes, affect the aggregation of amyloidogenic peptides such as amyloid-β (Aβ) peptides, whose aggregates are the hallmarks of Alzheimer's disease. Here, we combine experiments with all-atom molecular dynamics simulations in explicit solvent to explore the effects of neuronal ganglioside GM1, abundant in mammalian brains, on the aggregation of two principal isoforms of Aβ, Aβ40 and Aβ42. Our simulations show that free GM1 forms stable, highly water-soluble complexes with both isoforms, and nuclear magnetic resonance experiments support the formation of well-ordered, structurally compact GM1+Aβ complexes. By simulation, we also show that Aβ40 monomers display a preference for binding to GM1-containing hetero-oligomers over GM1-lacking homo-oligomers, while Aβ42 monomers have the opposite preference. These observations explain why GM1 dose-dependently inhibits Aβ40 aggregation but has no effect on Aβ42 aggregation, as assessed by thioflavin T fluorescence.
最近提出的脂质伴侣假说表明，游离脂质分子（未结合到膜上）会影响淀粉样肽（如淀粉样β肽，Aβ 肽）的聚集，而淀粉样肽的聚集是阿尔茨海默病的标志。在这里，我们结合实验和全原子分子动力学模拟在明确定义的溶剂中探索神经节苷脂 GM1 的作用，GM1 在哺乳动物大脑中含量丰富，对两种主要 Aβ 异构体（Aβ40 和 Aβ42）的聚集的影响。我们的模拟表明，游离 GM1 与两种异构体都形成稳定的、高水溶性的复合物，核磁共振实验支持有序的、结构紧凑的 GM1+Aβ 复合物的形成。通过模拟，我们还表明 Aβ40 单体显示出与含 GM1 的异寡聚物结合的偏好，而不是与缺乏 GM1 的同寡聚物结合，而 Aβ42 单体则具有相反的偏好。这些观察结果解释了为什么 GM1 剂量依赖性地抑制 Aβ40 聚集，但对 Aβ42 聚集没有影响，如通过硫黄素 T 荧光评估的那样。
