title: Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice.
abstract: Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta)-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 Abeta plaques. Cross-breeding generates triple transgenic ((triple)AD) mice that combine both pathologies in one model. To determine functional consequences of the combined Abeta 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 Abeta dependent, both at the protein and activity levels. Synergistic effects of Abeta 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 Abeta and tau in perishing mitochondria. Our study establishes a molecular link between Abeta and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.
authors.affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, 4025 Basel, Switzerland.
authors.forename: Virginie
authors.initials: V
authors.lastname: Rhein
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiesner
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.forename: Ginette
authors.initials: G
authors.lastname: Baysang
authors.forename: Fides
authors.initials: F
authors.lastname: Meier
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Horst
authors.initials: H
authors.lastname: Bluethmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Dröse
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.forename: Egemen
authors.initials: E
authors.lastname: Savaskan
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D010085:Oxidative Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D016875:tau Proteins