Single-Molecule Kinetic Observation of Antibody Interactions with Growing Amyloid β Fibrils
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.
Authors
- Hisashi Okumura (ORCID: https://orcid.org/0000-0003-3912-5604)
- Shigeyuki Miyajima (ORCID: https://orcid.org/0000-0002-5153-5537)
- Maho Yagi‐Utsumi (ORCID: https://orcid.org/0000-0001-8144-740X)
- Koichi Kato (ORCID: https://orcid.org/0000-0001-7187-9612)
- Katsuhiko Yanagisawa (ORCID: https://orcid.org/0000-0002-7324-7421)
- Takayuki Uchihashi (ORCID: https://orcid.org/0000-0002-0263-5312)
- Satoru Itoh (ORCID: https://orcid.org/0000-0002-2638-663X)
- Yui Kanaoka
Institutions
- University of Tsukuba (JP)
- National Institutes of Natural Sciences (JP)
- Nagoya City University (JP)
- Institute for Molecular Science (JP)
- National Center for Geriatrics and Gerontology (JP)
- Nagoya University (JP)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1021/jacs.4c08841
- Citations
- 9
- Primary Topic
- Protein Structure and Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- Naito Foundation
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Nagoya City University
- Japan Society for the Promotion of Science
- Precursory Research for Embryonic Science and Technology
- Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences