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

Virgine Rhein, Xiaomin Song, Andreas Weisner, Lars M. Ittner, Ginette Baysang, Fides Meier, Laurence Ozmen, Horst Bleuthmann, Stefan Droese, Ulrich Brandt, Egemen Savaskan, Christian Czech, Juergen Goetz, Anne Eckert

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    574 Citations (Scopus)


    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 APPswPS2N141I 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.
    Original languageEnglish
    Pages (from-to)20057-20062
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number47
    Publication statusPublished - 2009


    • Amyloid-beta peptide
    • Electron transport chain
    • Energy metabolism
    • Mitochondrial complexes
    • Tau protein


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