Journal article

Publication year: 2012

Pages: 1421-1433

Journal: Antioxidants & Redox Signaling

Volume number: 16

Issue number: 12

ISSN: 1523-0864

DOI Link: https://doi.org/10.1089/ars.2011.4173

Publisher: Mary Ann Liebert

Abstract: 
Aims: Intracellular amyloid beta (A beta) oligomers and extracellular A beta plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering A beta production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase A beta 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 A beta. Presence of an antioxidant rescued mitochondrial function and reduced formation of A beta, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing A beta 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 A beta was partly reduced by an antioxidant, indicating that A beta 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 A beta levels in vivo. Innovation: We show for the first time that mitochondrion-derived ROS are sufficient to trigger A beta 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 A beta 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. Antioxid. Redox Signal. 16, 1421-1433.

Harvard Citation style: Leuner, K., Schütt, T., Kurz, C., Eckert, S., Schiller, C., Occhipinti, A., et al. (2012) Mitochondrion-Derived Reactive Oxygen Species Lead to Enhanced Amyloid Beta Formation, Antioxidants & Redox Signaling, 16(12), pp. 1421-1433. https://doi.org/10.1089/ars.2011.4173

APA Citation style: Leuner, K., Schütt, T., Kurz, C., Eckert, S., Schiller, C., Occhipinti, A., Mai, S., Jendrach, M., Eckert, G., Kruse, S., Palmiter, R., Brandt, U., Dröse, S., Wittig, I., Willem, M., Haass, C., Reichert, A., & Müller, W. (2012). Mitochondrion-Derived Reactive Oxygen Species Lead to Enhanced Amyloid Beta Formation. Antioxidants & Redox Signaling. 16(12), 1421-1433. https://doi.org/10.1089/ars.2011.4173