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

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8766-8783
Number of pages18
JournalACS Nano
Volume13
Issue number8
DOIs
Publication statusPublished - 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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