Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation
| Autor: | Michael Willem, Sören Mai, Angelo Occhipinti, Stephan Dröse, Schamim H. Eckert, Ulrich Brandt, Carola Schiller, Richard D. Palmiter, Gunter P. Eckert, Ilka Wittig, Shane E. Kruse, Tanja Schütt, Kristina Leuner, Christian Haass, Christopher Kurz, Walter E. Müller, Marina Jendrach, Andreas S. Reichert |
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| Rok vydání: | 2012 |
| Předmět: |
analogs & derivatives [Antimycin A]
Physiology Clinical Biochemistry genetics [Amyloid Precursor Protein Secretases] Antimycin A antimycin Mitochondrion Biochemistry Mice chemistry.chemical_compound Aspartic Acid Endopeptidases metabolism [Reactive Oxygen Species] General Environmental Science chemistry.chemical_classification Microscopy Confocal biology Mitochondrial medicine Energy and redox metabolism [IGMD 8] drug effects [Mitochondria] metabolism [Aspartic Acid Endopeptidases] Flow Cytometry Mitochondria Cell biology Mitochondrial medicine [IGMD 8] ddc:540 pharmacology [Rotenone] Alzheimer's disease metabolism [Alzheimer Disease] Intracellular Amyloid beta metabolism [Amyloid beta-Peptides] Enzyme-Linked Immunosorbent Assay Forum Original Research CommunicationsMitochondria and Aging in Alzheimer's Disease (H. Reddy Ed.) Cell Line Alzheimer Disease Rotenone BACE1 protein human mental disorders Extracellular medicine Animals Humans pharmacology [Antimycin A] Molecular Biology Reactive oxygen species Amyloid beta-Peptides Cell Biology metabolism [Mitochondria] medicine.disease metabolism [Amyloid Precursor Protein Secretases] Mice Mutant Strains chemistry genetics [Aspartic Acid Endopeptidases] biology.protein General Earth and Planetary Sciences Amyloid Precursor Protein Secretases Reactive Oxygen Species Amyloid precursor protein secretase |
| Zdroj: | Antioxidants & Redox Signaling, 16, 1421-33 Antioxidants & redox signaling 16(12), 1421-1433 (2012). doi:10.1089/ars.2011.4173 Antioxidants & Redox Signaling, 16, 12, pp. 1421-33 |
| ISSN: | 1523-0864 |
| Popis: | Item does not contain fulltext AIMS: Intracellular amyloid beta (Abeta) oligomers and extracellular Abeta plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Abeta production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Abeta generation and thereby initiate a vicious cycle further impairing mitochondrial function. RESULTS: 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 Abeta. Presence of an antioxidant rescued mitochondrial function and reduced formation of Abeta, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Abeta 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 Abeta was partly reduced by an antioxidant, indicating that Abeta 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 Abeta levels in vivo. INNOVATION: We show for the first time that mitochondrion-derived ROS are sufficient to trigger Abeta production in vitro and in vivo. CONCLUSION: Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Abeta 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. |
| Databáze: | OpenAIRE |
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