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Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering

Author

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  • Jaekyun Jeon

    (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
    University of Maryland/National Institute of Standards and Technology)

  • Wai-Ming Yau

    (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

  • Robert Tycko

    (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health)

Abstract

Self-assembly of amyloid-β peptides leads to oligomers, protofibrils, and fibrils that are likely instigators of neurodegeneration in Alzheimer’s disease. We report results of time-resolved solid state nuclear magnetic resonance (ssNMR) and light scattering experiments on 40-residue amyloid-β (Aβ40) that provide structural information for oligomers that form on time scales from 0.7 ms to 1.0 h after initiation of self-assembly by a rapid pH drop. Low-temperature ssNMR spectra of freeze-trapped intermediates indicate that β-strand conformations within and contacts between the two main hydrophobic segments of Aβ40 develop within 1 ms, while light scattering data imply a primarily monomeric state up to 5 ms. Intermolecular contacts involving residues 18 and 33 develop within 0.5 s, at which time Aβ40 is approximately octameric. These contacts argue against β-sheet organizations resembling those found previously in protofibrils and fibrils. Only minor changes in the Aβ40 conformational distribution are detected as larger assemblies develop.

Suggested Citation

  • Jaekyun Jeon & Wai-Ming Yau & Robert Tycko, 2023. "Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38494-6
    DOI: 10.1038/s41467-023-38494-6
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    1. Erik W. Martin & Tyler S. Harmon & Jesse B. Hopkins & Srinivas Chakravarthy & J. Jeremías Incicco & Peter Schuck & Andrea Soranno & Tanja Mittag, 2021. "A multi-step nucleation process determines the kinetics of prion-like domain phase separation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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