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@ARTICLE{Leuner:136490,
      author       = {Leuner, Kristina and Schütt, Tanja and Kurz, Christopher
                      and Eckert, Schamim H and Schiller, Carola and Occhipinti,
                      Angelo and Mai, Sören and Jendrach, Marina and Eckert,
                      Gunter P and Kruse, Shane E and Palmiter, Richard D and
                      Brandt, Ulrich and Dröse, Stephan and Wittig, Ilka and
                      Willem, Michael and Haass, Christian and Reichert, Andreas S
                      and Müller, Walter E},
      title        = {{M}itochondrion-derived reactive oxygen species lead to
                      enhanced amyloid beta formation.},
      journal      = {Antioxidants $\&$ redox signaling},
      volume       = {16},
      number       = {12},
      issn         = {1523-0864},
      address      = {Larchmont, NY},
      publisher    = {Liebert},
      reportid     = {DZNE-2020-02812},
      pages        = {1421-1433},
      year         = {2012},
      abstract     = {Intracellular amyloid beta (Aβ) oligomers and
                      extracellular Aβ plaques are key players in the progression
                      of sporadic Alzheimer's disease (AD). Still, the molecular
                      signals triggering Aβ production are largely unclear. We
                      asked whether mitochondrion-derived reactive oxygen species
                      (ROS) are sufficient to increase Aβ generation and thereby
                      initiate a vicious cycle further impairing mitochondrial
                      function.Complex I and III dysfunction was induced in a cell
                      model using the respiratory inhibitors rotenone and
                      antimycin, resulting in mitochondrial dysfunction and
                      enhanced ROS levels. Both treatments lead to elevated levels
                      of Aβ. Presence of an antioxidant rescued mitochondrial
                      function and reduced formation of Aβ, demonstrating that
                      the observed effects depended on ROS. Conversely, cells
                      overproducing Aβ showed impairment of mitochondrial
                      function such as comprised mitochondrial respiration,
                      strongly altered morphology, and reduced intracellular
                      mobility of mitochondria. Again, the capability of these
                      cells to generate Aβ was partly reduced by an antioxidant,
                      indicating that Aβ formation was also ROS dependent.
                      Moreover, mice with a genetic defect in complex I, or AD
                      mice treated with a complex I inhibitor, showed enhanced Aβ
                      levels in vivo.We show for the first time that
                      mitochondrion-derived ROS are sufficient to trigger Aβ
                      production in vitro and in vivo.Several lines of evidence
                      show that mitochondrion-derived ROS result in enhanced
                      amyloidogenic amyloid precursor protein processing, and that
                      Aβ itself leads to mitochondrial dysfunction and increased
                      ROS levels. We propose that starting from mitochondrial
                      dysfunction a vicious cycle is triggered that contributes to
                      the pathogenesis of sporadic AD.},
      keywords     = {Alzheimer Disease: metabolism / Amyloid Precursor Protein
                      Secretases: genetics / Amyloid Precursor Protein Secretases:
                      metabolism / Amyloid beta-Peptides: metabolism / Animals /
                      Antimycin A: analogs $\&$ derivatives / Antimycin A:
                      pharmacology / Aspartic Acid Endopeptidases: genetics /
                      Aspartic Acid Endopeptidases: metabolism / Cell Line /
                      Enzyme-Linked Immunosorbent Assay / Flow Cytometry / Humans
                      / Mice / Mice, Mutant Strains / Microscopy, Confocal /
                      Mitochondria: drug effects / Mitochondria: metabolism /
                      Reactive Oxygen Species: metabolism / Rotenone: pharmacology
                      / Amyloid beta-Peptides (NLM Chemicals) / Reactive Oxygen
                      Species (NLM Chemicals) / Rotenone (NLM Chemicals) /
                      antimycin (NLM Chemicals) / Antimycin A (NLM Chemicals) /
                      Amyloid Precursor Protein Secretases (NLM Chemicals) /
                      Aspartic Acid Endopeptidases (NLM Chemicals) / BACE1
                      protein, human (NLM Chemicals)},
      cin          = {Ext LMU / AG Haass old},
      ddc          = {540},
      cid          = {I:(DE-2719)5000048 / I:(DE-2719)1110007},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22229260},
      pmc          = {pmc:PMC3329950},
      doi          = {10.1089/ars.2011.4173},
      url          = {https://pub.dzne.de/record/136490},
}