Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease
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Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the age-dependent accumulation of beta-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of beta-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COX-deficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKIIalpha promoter-driven Cre-recombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in Abeta42 level, beta-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments.
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Brains of mice engineered to overproduce mutant APP and PS1 in the setting of less COX holoenzyme show reduced plaque deposition, less fibrillar Aβ, and less oxidative stress than APP-PS1 mice that can freely produce COX.
“The brains of these mice show reduced plaque deposition, less fibrillar Aβ, and less oxidative stress than APP-PS1 mice that can freely produce COX [175, 176].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [175]
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- Authors
- Fukui, H., Diaz, F., Garcia, S., & Moraes, C. T.
- Affiliations
- University of Miami (US)
- Departments of †Neurology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-08-28
- Volume
- 104
- Issue
- 35
- Pages
- 14163-14168
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1955773
- OpenAlex
- W2023378584
- Cited by
- 185
- References
- 45
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 13 · 2023: 11 · 2022: 9 · 2021: 9 · 2020: 7 · 2019: 8 · 2018: 9 · 2017: 10 · 2016: 8 · 2015: 5 · 2014: 8 · 2013: 8 · 2012: 13
- FWCI
- 8.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (R01EY010804)
- National Cancer Institute (R01CA085700)
- National Institute of Neurological Disorders and Stroke (R01-NS41777, R01NS041777)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- cytochrome c oxidase deficiency, Alzheimer's disease, amyloid-beta, amyloid plaques, COX10, mitochondrial respiratory function, oxidative stress, reactive oxygen species, amyloid precursor protein, presenilin 1, beta-secretase, mouse model
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Citrate (si)-Synthase, Electron Transport Complex IV, Disease Models, Animal, Mitochondria, Neurons, Oxygen Consumption, Peroxides, Mice, Knockout, Oxidative Stress, Mice
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