Diverse Structural Conversion and Aggregation Pathways of Alzheimer's 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

doi:10.1021/acsnano.9b01578

Diverse Structural Conversion and Aggregation Pathways of Alzheimer's 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 RamamoorthyYoung Ho Lee

Creative Interdisciplinary Research Division

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25 Citations (Scopus)

Abstract

Complex amyloid aggregation of amyloid-β (1-40) (Aβ_1-40) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ_1-40 aggregation with macroscopic viewpoints through tuning its initial structure and solubility. Partial helical structures of Aβ_1-40 induced by low solvent polarity accelerated cytotoxic Aβ_1-40 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 Aβ_1-40 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.

Original language	English
Pages (from-to)	8766-8783
Number of pages	18
Journal	ACS Nano
Volume	13
Issue number	8
DOIs	https://doi.org/10.1021/acsnano.9b01578
Publication status	Published - 2019 Aug 27

Keywords

Alzheimer's disease
aggregation pathway
amyloid fibril
amyloid β
helical structure
phase diagram
protein misfolding and aggregation

ASJC Scopus subject areas

Materials Science(all)
Engineering(all)
Physics and Astronomy(all)

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10.1021/acsnano.9b01578

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Lin, Y., Sahoo, B. R., Ozawa, D., Kinoshita, M., Kang, J., Lim, M. H., Okumura, M., Huh, Y. H., Moon, E., Jang, J. H., Lee, H. J., Ryu, K. Y., Ham, S., Won, H. S., Ryu, K. S., Sugiki, T., Bang, J. K., Hoe, H. S., Fujiwara, T., ... Lee, Y. H. (2019). Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40). ACS Nano, 13(8), 8766-8783. https://doi.org/10.1021/acsnano.9b01578

Lin, Y, Sahoo, BR, Ozawa, D, Kinoshita, M, Kang, J, Lim, MH, Okumura, M, Huh, YH, Moon, E, Jang, JH, Lee, HJ, Ryu, KY, Ham, S, Won, HS, Ryu, KS, Sugiki, T, Bang, JK, Hoe, HS, Fujiwara, T, Ramamoorthy, A & Lee, YH 2019, 'Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40)', ACS Nano, vol. 13, no. 8, pp. 8766-8783. https://doi.org/10.1021/acsnano.9b01578

@article{6a61078a3aa64c9b86c2b38fc75e0426,

title = "Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40)",

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.",

keywords = "Alzheimer's disease, aggregation pathway, amyloid fibril, amyloid β, helical structure, phase diagram, protein misfolding and aggregation",

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

note = "Funding Information: We thank Prof. Yuji Goto (Osaka University, Japan) for providing instruments. We also thank Dr. Mayu Terakawa (Columbia University, USA) for support of TEM measurements. This work was supported by the Grant-in-Aid for Young Scientists (B) (15K18518 and 25870407, Japan) (Y.-H.L.), the Korea Basic Science Institute grant (T38624) (Y.-H.L.), the National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF-PG2018123 and NRF-PG2019046) (Y.-H.L.), a National Research Council of Science & Technology (NST) grant funded by the Korean government (MSIP) (CAP-17-05-KIGAM) (Y.-H.L.), the National Institutes of Health grant (AG048934) (A.R.), an NRF grant funded by the Korean government (NRF-2017R1A2B3002585) (M.H.L.), the Samsung Science and Technology Foundation (SSTF-BA1401-13) (S.H.), and the basic research program of Korea Brain Research Institute funded by the Ministry of Science, ICT & Future Planning (19-BR-02-02) (H.S.H.). Publisher Copyright: Copyright {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = aug,

day = "27",

doi = "10.1021/acsnano.9b01578",

language = "English",

volume = "13",

pages = "8766--8783",

journal = "ACS Nano",

issn = "1936-0851",

publisher = "American Chemical Society",

number = "8",

}

TY - JOUR

T1 - Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40)

AU - Lin, Yuxi

AU - Sahoo, Bikash R.

AU - Ozawa, Daisaku

AU - Kinoshita, Misaki

AU - Kang, Juhye

AU - Lim, Mi Hee

AU - Okumura, Masaki

AU - Huh, Yang Hoon

AU - Moon, Eunyoung

AU - Jang, Jae Hyuck

AU - Lee, Hyun Ju

AU - Ryu, Ka Young

AU - Ham, Sihyun

AU - Won, Hyung Sik

AU - Ryu, Kyoung Seok

AU - Sugiki, Toshihiko

AU - Bang, Jeong Kyu

AU - Hoe, Hyang Sook

AU - Fujiwara, Toshimichi

AU - Ramamoorthy, Ayyalusamy

AU - Lee, Young Ho

N1 - Funding Information: We thank Prof. Yuji Goto (Osaka University, Japan) for providing instruments. We also thank Dr. Mayu Terakawa (Columbia University, USA) for support of TEM measurements. This work was supported by the Grant-in-Aid for Young Scientists (B) (15K18518 and 25870407, Japan) (Y.-H.L.), the Korea Basic Science Institute grant (T38624) (Y.-H.L.), the National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF-PG2018123 and NRF-PG2019046) (Y.-H.L.), a National Research Council of Science & Technology (NST) grant funded by the Korean government (MSIP) (CAP-17-05-KIGAM) (Y.-H.L.), the National Institutes of Health grant (AG048934) (A.R.), an NRF grant funded by the Korean government (NRF-2017R1A2B3002585) (M.H.L.), the Samsung Science and Technology Foundation (SSTF-BA1401-13) (S.H.), and the basic research program of Korea Brain Research Institute funded by the Ministry of Science, ICT & Future Planning (19-BR-02-02) (H.S.H.). Publisher Copyright: Copyright © 2019 American Chemical Society.

PY - 2019/8/27

Y1 - 2019/8/27

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - aggregation pathway

KW - amyloid fibril

KW - amyloid β

KW - helical structure

KW - phase diagram

KW - protein misfolding and aggregation

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DO - 10.1021/acsnano.9b01578

M3 - Article

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AN - SCOPUS:85071712775

SN - 1936-0851

VL - 13

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EP - 8783

JO - ACS Nano

JF - ACS Nano

IS - 8

ER -

Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40)

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Keywords

ASJC Scopus subject areas

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