| Mitochondria-derived ROS lead to enhanced amyloid beta formation. | |
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MedLine Citation:
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PMID: 22229260 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Aims: Intracellular amyloid beta (Aß) oligomers and extracellular Aß plaques are key players in the progression of sporadic Alzheimer disease (AD). Still, the molecular signals triggering Aß production are largely unclear. We asked whether mitochondria-derived reactive oxygen species (ROS) are sufficient to increase Aß generation and thereby initiate a vicious cycle further impairing mitochondrial function. Results: Complex I and III dysfunction were 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 Aß. Presence of an antioxidant rescued mitochondrial function and reduced formation of Aß demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Aß 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 Aß was partly reduced by an antioxidant indicating that Aß 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 Aß levels in vivo. Innovation: We show for the first time that mitochondria-derived ROS are sufficient to trigger Aß production in vitro and in vivo. Conclusion: Several lines of evidence show that mitochondria-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aß 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. |
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Authors:
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Kristina Leuner; Tanja Schütt; Christopher Kurz; Schamim H Eckert; Carola Schiller; Angelo Occhipinti; Sören Mai; Marina Jendrach; Gunter P Eckert; Shane E Kruse; Richard D Palmiter; Ulrich Brandt; Stefan Dröse; Ilka Wittig; Micheal Willem; Christian Haass; Andreas S Reichert; Walter E Mueller |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-9 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: - ISSN: 1557-7716 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Goethe University, Pharmacology, Frankfurt, Germany; Leuner@em.uni-frankfurt.de. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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