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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-11, Vol.106 (47), p.20057-20062
• Main Authors: Rhein, Virginie, Song, Xiaomin, Wiesner, Andreas, Ittner, Lars M, Baysang, Ginette, Meier, Fides, Ozmen, Laurence, Bluethmann, Horst, Dröse, Stefan, Brandt, Ulrich, Savaskan, Egemen, Czech, Christian, Götz, Jürgen, Eckert, Anne
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimers disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; Biological Sciences; Humans; Mass Spectrometry - methods; Membrane Potential, Mitochondrial - physiology; Mice; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Neurons; Oxidative Phosphorylation; Oxygen consumption; Pathology; Protein precursors; Proteomics; Reactive Oxygen Species - metabolism; Respiration; tau Proteins - genetics; tau Proteins - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0905529106

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.