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Copper-Dependent Inhibition of Human Cytochrome c Oxidase by a Dimeric Conformer of Amyloid-β1-42
Open accessAbstract
In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms of intracellular amyloid-beta (Abeta) generation and toxicity. Here we investigated the inhibitory potential of the 42 amino acid Abeta peptide (Abeta1-42) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic Abeta1-42 specifically inhibited the terminal complex cytochrome c oxidase (COX) in a dose-dependent manner that was dependent on the presence of Cu2+ and specific "aging" of the Abeta1-42 solution. Maximal COX inhibition occurred when using Abeta1-42 solutions aged for 3-6 h at 30 degrees C. The level of Abeta1-42-mediated COX inhibition increased with aging time up to approximately 6 h and then declined progressively with continued aging to 48 h. Photo-induced cross-linking of unmodified proteins followed by SDS-PAGE analysis revealed dimeric Abeta as the only Abeta species to provide significant temporal correlation with the observed COX inhibition. Analysis of brain and liver from an Alzheimer's model mouse (Tg2576) revealed abundant Abeta immunoreactivity within the brain mitochondria fraction. Our data indicate that endogenous Abeta is associated with brain mitochondria and that Abeta1-42, possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu2+. We conclude that Cu2+-dependent Abeta-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.
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“accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [64]
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Metadata
- Authors
- Crouch, P. J., Blake, R., Duce, J. A., Ciccotosto, G. D., Li, Q.-X., Barnham, K. J., Curtain, C. C., Cherny, R. A., Cappai, R., Dyrks, T., Masters, C. L., & Trounce, I. A.
- Affiliations
- The University of Melbourne (AU)
- Mental Health Research Institute (AU)
- Corresponding author
- Trounce, Ian A.
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-01-19
- Volume
- 25
- Issue
- 3
- Pages
- 672-679
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6725334
- OpenAlex
- W2143582172
- Cited by
- 327
- References
- 47
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 11 · 2017: 24 · 2016: 15 · 2015: 17 · 2014: 13 · 2013: 21 · 2012: 22
- FWCI
- 13.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- amyloid-beta 42, cytochrome c oxidase, copper ions, enzyme inhibition, Alzheimer's disease, mitochondrial electron transport chain, neurodegeneration, brain mitochondria
- MeSH terms
- Animals, Brain, Cells, Cultured, Copper, Electron Transport Complex IV, Humans, Mice, Transgenic, Mitochondria, Mitochondria, Liver, Peptide Fragments, Time Factors, Amyloid beta-Peptides, Multiprotein Complexes, Mice
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