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Cited by 1,111Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils

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Ahmed, Mahiuddin, Davis, Judianne, Aucoin, Darryl, Sato, Takeshi, Ahuja, Shivani, Aimoto, Saburo, Elliott, James I, Van Nostrand, William E +1 more·2010·Nature Structural & Molecular Biology
DOI 10.1038/nsmb.1799PMC PMC2922021
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Abstract

The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.

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Authors
Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliott, J. I., Van Nostrand, W. E., & Smith, S. O.
Affiliations
  • Stony Brook University (US)
  • Institute for Protein Research, The University of Osaka (JP)
  • Yale University (US)
Corresponding author
Smith, Steven O
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2010-04-11
Volume
17
Issue
5
Pages
561-567
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/nsmb.1799
PMC
PMC2922021
OpenAlex
W1973479349
Cited by
1,111
References
6
Citations by year
2026: 46 · 2025: 47 · 2024: 53 · 2023: 69 · 2022: 50 · 2021: 70 · 2020: 79 · 2019: 78 · 2018: 91 · 2017: 91 · 2016: 97 · 2015: 81 · 2014: 74 · 2013: 61 · 2012: 59
FWCI
39.86
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health (1s10rr013889-01)
  • U.S. Public Health Service (DBI-9977553)
  • National Institute on Aging (R01AG027317)
  • National Institute of General Medical Sciences (T32GM008444)
  • National Institute of Neurological Disorders and Stroke (R01-NS35781, R01NS035781)
  • National Center for Research Resources (S10 RR 13889)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
amyloid-beta 42, peptide oligomers, neurotoxicity, Alzheimer's disease, amyloid plaques, pentamer, parallel beta-sheet, protofibrils, turn conformation, cortical neurons
MeSH terms
Alzheimer Disease, Amino Acid Sequence, Animals, Cell Survival, Cells, Cultured, Cold Temperature, Models, Molecular, Molecular Sequence Data, Neurons, Peptide Fragments, Salts, Amyloid beta-Peptides, Protein Structure, Secondary, Nuclear Magnetic Resonance, Biomolecular, Mice, Protein Multimerization

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