Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 465-8603, Japan.
Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki, Aichi 444-8787, Japan.
J Am Chem Soc. 2024 Nov 20;146(46):31518-31528. doi: 10.1021/jacs.4c08841. Epub 2024 Oct 24.
Understanding the dynamic assembly process of amyloid β (Aβ) during fibril formation is essential for developing effective therapeutic strategies against Alzheimer's disease. Here, we employed high-speed atomic force microscopy to observe the growth of Aβ fibrils at the single-molecule level, focusing specifically on their interaction with anti-Aβ antibodies. Our findings show that fibril growth consists of intermittent periods of elongation and pausing, which are dictated by the alternating addition of Aβ monomers to protofilaments. We highlight the distinctive interaction of antibody 4396C, which specifically binds to the fibril ends in the paused state, suggesting a unique mechanism to hinder fibril elongation. Through real-time visualization of fibril growth and antibody interactions combined with molecular simulation, this study provides a refined understanding of Aβ assembly during fibril formation and suggests novel strategies for Alzheimer's therapy aimed at inhibiting the fibril elongation.
了解淀粉样蛋白β（Aβ）在纤维形成过程中的动态组装过程对于开发针对阿尔茨海默病的有效治疗策略至关重要。在这里，我们采用高速原子力显微镜在单分子水平上观察 Aβ纤维的生长，特别关注它们与抗 Aβ 抗体的相互作用。我们的研究结果表明，纤维的生长由伸长和暂停的间歇性阶段组成，这是由 Aβ 单体交替添加到原纤维上决定的。我们强调了抗体 4396C 的独特相互作用，该抗体在暂停状态下特异性结合纤维末端，表明存在一种独特的机制来阻碍纤维的伸长。通过实时可视化纤维的生长和抗体的相互作用结合分子模拟，本研究提供了对纤维形成过程中 Aβ 组装的精细理解，并提出了针对阿尔茨海默病治疗的新策略，旨在抑制纤维的伸长。
