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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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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Conflicting results have been reported for Cu2+-mediated Aβ aggregation.
“Several studies showed that Zn2+ promotes formation of nonfibrillar aggregates,16,29–31 yet conflicting results have been reported for the Cu2+-mediated Aβ aggregation.21,28,32,33”
From The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity (2013) · cites this paper as [33]
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“Oligomeric and aggregated species may be favored over fiber formation (19), however, formation of amorphous aggregates, fibrils, or oligomers is very dependent on the particular experimental conditions in vitro (20).”
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InfluentialCopper mediated amyloid-β binding to Transthyretin
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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)
- PMC
- PMC3009880
- 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
- hybrid
- doi.org
- Licence
- 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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