Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice
Open accessAbstract
Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ)-containing plaques, neurofibrillary tangles, and neuron and synapse loss. Tangle formation has been reproduced in P301L tau transgenic pR5 mice, whereas APP sw PS2 N141I double-transgenic APP152 mice develop Aβ plaques. Cross-breeding generates triple transgenic ( triple AD) mice that combine both pathologies in one model. To determine functional consequences of the combined Aβ and tau pathologies, we performed a proteomic analysis followed by functional validation. Specifically, we obtained vesicular preparations from triple AD mice, the parental strains, and nontransgenic mice, followed by the quantitative mass-tag labeling proteomic technique iTRAQ and mass spectrometry. Within 1,275 quantified proteins, we found a massive deregulation of 24 proteins, of which one-third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Notably, deregulation of complex I was tau dependent, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. Synergistic effects of Aβ and tau were evident in 8-month-old triple AD mice as only they showed a reduction of the mitochondrial membrane potential at this early age. At the age of 12 months, the strongest defects on OXPHOS, synthesis of ATP, and reactive oxygen species were exhibited in the triple AD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in perishing mitochondria. Our study establishes a molecular link between Aβ and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.
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Mitochondria dysfunction has been demonstrated in tau P301L transgenic mice.
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- Authors
- Rhein, V., Song, X., Wiesner, A., Ittner, L. M., Baysang, G., Meier, F., Ozmen, L., Bluethmann, H., Dröse, S., Brandt, U., Savaskan, E., Czech, C., Götz, J., & Eckert, A.
- Affiliations
- University of Basel (CH)
- Macquarie University (AU)
- The University of Sydney (AU)
- F. Hoffmann-La Roche AG (CH)
- Goethe University Frankfurt (DE)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-11-24
- Volume
- 106
- Issue
- 47
- Pages
- 20057-20062
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2774257
- OpenAlex
- W2120701804
- Cited by
- 655
- References
- 5
- Citations by year
- 2026: 18 · 2025: 28 · 2024: 20 · 2023: 45 · 2022: 37 · 2021: 48 · 2020: 47 · 2019: 41 · 2018: 42 · 2017: 33 · 2016: 40 · 2015: 42 · 2014: 42 · 2013: 37 · 2012: 45
- FWCI
- 29.60
- 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)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310000)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta, tau protein, triple transgenic mice, oxidative phosphorylation, mitochondrial dysfunction, complex I, cytochrome c oxidase, mitochondrial membrane potential, reactive oxygen species, ATP production, neurofibrillary tangles
- MeSH terms
- Alzheimer Disease, Animals, Humans, Mice, Transgenic, Mitochondria, Oxidative Phosphorylation, Mass Spectrometry, Amyloid beta-Peptides, tau Proteins, Reactive Oxygen Species, Mice, Membrane Potential, Mitochondrial
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