journal article·2019-08-27Open access

Diverse Structural Conversion and Aggregation Pathways of Alzheimerʼs Amyloid-β (1–40)

Yuxi Lin, Bikash R. Sahoo, Daisaku Ozawa, Misaki Kinoshita, Juhye Kang, Mi Hee Lim, Masaki Okumura, Yang Hoon Huh, Eunyoung Moon, Jae Hyuck Jang, Hyun-Ju Lee, Ka-Young Ryu, Sihyun Ham, Hyung-Sik Won, Kyoung-Seok Ryu, Toshihiko Sugiki, Jeong Kyu Bang, Hyang-Sook Hoe, Toshimichi Fujiwara, Ayyalusamy Ramamoorthy, Young-Ho Lee

ACS Nano· Volume 13· Issue 8

Abstract

Complex amyloid aggregation of amyloid-β (1–40) (Aβ1–40) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ1–40 aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aβ1–40 induced by low solvent polarity accelerated cytotoxic Aβ1–40 amyloid fibrillation, while predominantly helical folds did not aggregate. Changes in the solvent polarity caused a rapid formation of β-structure-rich protofibrils or oligomers via aggregation-prone helical structures. Modulation of the pH and salt concentration transformed oligomers to protofibrils, which proceeded to amyloid formation. We reveal diverse molecular mechanisms underlying Aβ1–40 aggregation with conceptual energy diagrams and propose that aggregation-prone partial helical structures are key to inducing amyloidogenesis. We demonstrate that context-dependent protein aggregation is comprehensively understood using the macroscopic phase diagram, which provides general insights into differentiation of amyloid formation and phase separation from unfolded and folded structures.
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Research context

OpenAlex topics: Alzheimer's disease research and treatments · Computational Drug Discovery Methods · Protein Structure and Dynamics

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemistry, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 04310, South Korea

Biophysics Program and Department of Chemistry, Biomedical Engineering, and Macromolecular Science and Engineering, University of Michigan, Ann Arbor, Michigan 48109-1055, United States

Department of Neurotherapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, 6-3 Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-8578, Japan

Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 34141, South Korea

Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea

Department of Neural Development and Disease, Korea Brain Research Institute, 61 Cheomdan-ro, Dong-gu, Daegu 41068, South Korea

Department of Biotechnology, Research Institute and College of Biomedical and Health Science, Konkuk University, Chungju, Chungbuk 27478, South Korea

Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan

Bio-Analytical Science, University of Science and Technology, Daejeon 34113, South Korea

Funding

National Research Council of Science and Technology · National Research Foundation of Korea · Korea Basic Science Institute · Japan Society for the Promotion of Science · National Institute on Aging · Ministry of Science, ICT and Future Planning · Samsung Science and Technology Foundation

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