Cited by 199Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

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Sarell, Claire J., Wilkinson, Shane R., Viles, John H.·2010·Journal of Biological Chemistry

Abstract

A role for Cu(2+) ions in Alzheimer disease is often disputed, as it is believed that Cu(2+) ions only promote nontoxic amorphous aggregates of amyloid-β (Aβ). In contrast with currently held opinion, we show that the presence of substoichiometric levels of Cu(2+) ions in fact doubles the rate of production of amyloid fibers, accelerating both the nucleation and elongation of fiber formation. We suggest that binding of Cu(2+) ions at a physiological pH causes Aβ to approach its isoelectric point, thus inducing self-association and fiber formation. We further show that Cu(2+) ions bound to Aβ are consistently more toxic to neuronal cells than Aβ in the absence of Cu(2+) ions, whereas Cu(2+) ions in the absence of Aβ are not cytotoxic. The degree of Cu-Aβ cytotoxicity correlates with the levels of Cu(2+) ions that accelerate fiber formation. We note the effect appears to be specific for Cu(2+) ions as Zn(2+) ions inhibit the formation of fibers. An active role for Cu(2+) ions in accelerating fiber formation and promoting cell death suggests impaired copper homeostasis may be a risk factor in Alzheimer disease.

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Authors
Sarell, C. J., Wilkinson, S. R., & Viles, J. H.
Affiliations
Queen Mary University of London (GB)
Corresponding author
Viles, John H.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-12
Volume
285
Issue
53
Pages
41533-41540
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1985891852
Cited by
199
References
69
Citations by year
2026: 9 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 18 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 16 · 2017: 16 · 2016: 12 · 2015: 17 · 2014: 9 · 2013: 12 · 2012: 18
FWCI
9.53
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council (BB/D005027/1)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta, copper ions, Alzheimer's disease, amyloid fibril formation, copper binding, isoelectric point, zinc ions, copper homeostasis, metal-protein interactions
MeSH terms
Alzheimer Disease, Animals, Biophysics, Cell Survival, Copper, Hydrogen-Ion Concentration, Ions, Isoelectric Point, Kinetics, Neurons, Zinc, Amyloid beta-Peptides, PC12 Cells, Protein Folding, Microscopy, Electron, Transmission, Rats

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