Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice
Open accessAbstract
Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.
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Mitochondria dysfunction has been demonstrated in tau P301L transgenic mice.
“Mitochondria dysfunction has been demonstrated in tau P301L transgenic mice (92 -94)”
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- Authors
- David, D. C., Hauptmann, S., Scherping, I., Schuessel, K., Keil, U., Rizzu, P., Ravid, R., Dröse, S., Brandt, U., Müller, W. E., Eckert, A., & Götz, J.
- Affiliations
- University of Zurich (CH)
- Goethe University Frankfurt (DE)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Netherlands Brain Bank (NL)
- Universitäre Psychiatrische Kliniken Basel (CH)
- Corresponding author
- Götz, Jürgen
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-06
- Volume
- 280
- Issue
- 25
- Pages
- 23802-23814
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2136673626
- Cited by
- 447
- References
- 10
- Citations by year
- 2026: 14 · 2025: 28 · 2024: 14 · 2023: 25 · 2022: 30 · 2021: 34 · 2020: 41 · 2019: 21 · 2018: 22 · 2017: 16 · 2016: 18 · 2015: 14 · 2014: 16 · 2013: 15 · 2012: 24
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- Deutsche Forschungsgemeinschaft (SFB 472)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- EMDO Stiftung
- Olga Mayenfisch Stiftung
- 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 › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- P301L tau, tauopathy, mitochondrial dysfunction, mitochondrial complex V, complex I, oxidative stress, reactive oxygen species, lipid peroxidation, antioxidant enzymes, amyloid-beta, neurofibrillary tangles, frontotemporal dementia with parkinsonism linked to chromosome 17, mitochondrial respiration, ATP production, transgenic mice
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Mitochondria, Mass Spectrometry, Electrophoresis, Gel, Two-Dimensional, Up-Regulation, tau Proteins, Mice
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