Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

Rhein, Virginie, Song, Xiaomin, Wiesner, Andreas, Ittner, Lars M., Baysang, Ginette, Meier, Fides, Ozmen, Laurence, Bluethmann, Horst, Drose, Stefan, Brandt, Ulrich, Savaskan, Egemen, Czech, Christian, Gotz, Jurgen and Eckert, Anne (2009) Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice. Proceedings of the National Academy of Sciences of the United States of America, 106 47: 20057-20062. doi:10.1073/pnas.0905529106


Author Rhein, Virginie
Song, Xiaomin
Wiesner, Andreas
Ittner, Lars M.
Baysang, Ginette
Meier, Fides
Ozmen, Laurence
Bluethmann, Horst
Drose, Stefan
Brandt, Ulrich
Savaskan, Egemen
Czech, Christian
Gotz, Jurgen
Eckert, Anne
Title Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2009-11-24
Sub-type Article (original research)
DOI 10.1073/pnas.0905529106
Open Access Status Not Open Access
Volume 106
Issue 47
Start page 20057
End page 20062
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
Abstract 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 swPS2 N141I double-transgenic APP152 mice develop Aβ plaques. Cross-breeding generates triple transgenic ( tripleAD) 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 tripleAD 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 tripleAD 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 tripleAD 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.
Keyword Amyloid-beta peptide
Electron transport chain
Energy metabolism
Mitochondrial complexes
Tau protein
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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