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标题：Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice
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作者：Virginie Rhein ; Xiaomin Song ; Andreas Wiesner 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：47
页码：20057-20062
DOI：10.1073/pnas.0905529106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alzheimer's disease (AD) is characterized by amyloid-beta (A{beta})-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 A{beta} plaques. Cross-breeding generates triple transgenic (tripleAD) mice that combine both pathologies in one model. To determine functional consequences of the combined A{beta} 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 A{beta} dependent, both at the protein and activity levels. Synergistic effects of A{beta} 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 A{beta} and tau in perishing mitochondria. Our study establishes a molecular link between A{beta} and tau protein in AD pathology in vivo, illustrating the potential of quantitative proteomics.
关键词：amyloid-beta peptide ; electron transport chain ; energy metabolism ; mitochondrial complexes ; tau protein