Cited by 68Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchPrion Diseases and Protein Misfolding

Quantitative analysis of co-oligomer formation by amyloid-beta peptide isoforms.

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Iljina, Marija, Garcia, Gonzalo A., Dear, Alexander J., Flint, Jennie, Narayan, Priyanka, Michaels, Thomas C. T., Dobson, Christopher M., Frenkel, Daan +2 more·2016·Scientific Reports

Abstract

Multiple isoforms of aggregation-prone proteins are present under physiological conditions and have the propensity to assemble into co-oligomers with different properties from self-oligomers, but this process has not been quantitatively studied to date. We have investigated the amyloid-β (Aβ) peptide, associated with Alzheimer's disease, and the aggregation of its two major isoforms, Aβ40 and Aβ42, using a statistical mechanical modelling approach in combination with in vitro single-molecule fluorescence measurements. We find that at low concentrations of Aβ, corresponding to its physiological abundance, there is little free energy penalty in forming co-oligomers, suggesting that the formation of both self-oligomers and co-oligomers is possible under these conditions. Our model is used to predict the oligomer concentration and size at physiological concentrations of Aβ and suggests the mechanisms by which the ratio of Aβ42 to Aβ40 can affect cell toxicity. An increased ratio of Aβ42 to Aβ40 raises the fraction of oligomers containing Aβ42, which can increase the hydrophobicity of the oligomers and thus promote deleterious binding to the cell membrane and increase neuronal damage. Our results suggest that co-oligomers are a common form of aggregate when Aβ isoforms are present in solution and may potentially play a significant role in Alzheimer's disease.

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Authors
Iljina, M., Garcia, G. A., Dear, A. J., Flint, J., Narayan, P., Michaels, T. C. T., Dobson, C. M., Frenkel, D., Knowles, T. P. J., & Klenerman, D.
Affiliations
University of Cambridge (GB)
Corresponding author
  • Knowles, Tuomas P. J.
  • Klenerman, David
Venue
Scientific Reports
Published
2016-06-27
Volume
6
Issue
1
Pages
28658-28658
ISSN
2045-2322 (ISSN-L)
OpenAlex
W2473103627
Cited by
68
References
60
Citations by year
2026: 6 · 2025: 4 · 2024: 12 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 9 · 2019: 6 · 2018: 14 · 2017: 2
FWCI
5.90
Type
journal article
Language
en
Open access
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Frances and Augustus Newman Foundation
  • Schiff Foundation
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, Aβ40, amyloid-beta 42, co-oligomers, protein aggregation, Alzheimer's disease, single-molecule fluorescence, oligomer size distribution, cell membrane binding, neurotoxicity, isoform ratio
MeSH terms
Alzheimer Disease, Humans, Models, Chemical, Peptide Fragments, Amyloid beta-Peptides, Protein Isoforms, Protein Multimerization

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