Single-Molecule Kinetic Observation of Antibody Interactions with Growing Amyloid β Fibrils

作者：Maho Yagi‐Utsumi, Yui Kanaoka, Shogo Miyajima, Satoru Itoh, Katsuhiko Yanagisawa, Hisashi Okumura, Takayuki Uchihashi, Koichi Kato · 发表于：Journal of the American Chemical Society · 年份：2024 · DOI：10.1021/jacs.4c08841 · 被引用次数：10 · 研究领域：Protein Structure and Dynamics、Supramolecular Self-Assembly in Materials、Alzheimer's disease research and treatments

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.