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000136490 0247_ $$2doi$$a10.1089/ars.2011.4173
000136490 0247_ $$2pmid$$apmid:22229260
000136490 0247_ $$2pmc$$apmc:PMC3329950
000136490 0247_ $$2ISSN$$a1523-0864
000136490 0247_ $$2ISSN$$a1557-7716
000136490 037__ $$aDZNE-2020-02812
000136490 041__ $$aEnglish
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000136490 1001_ $$0P:(DE-HGF)0$$aLeuner, Kristina$$b0$$eCorresponding author
000136490 245__ $$aMitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation.
000136490 260__ $$aLarchmont, NY$$bLiebert$$c2012
000136490 264_1 $$2Crossref$$3print$$bMary Ann Liebert Inc$$c2012-06-15
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000136490 520__ $$aIntracellular amyloid beta (Aβ) oligomers and extracellular Aβ plaques are key players in the progression of sporadic Alzheimer's disease (AD). Still, the molecular signals triggering Aβ production are largely unclear. We asked whether mitochondrion-derived reactive oxygen species (ROS) are sufficient to increase Aβ generation and thereby initiate a vicious cycle further impairing mitochondrial function.Complex I and III dysfunction was induced in a cell model using the respiratory inhibitors rotenone and antimycin, resulting in mitochondrial dysfunction and enhanced ROS levels. Both treatments lead to elevated levels of Aβ. Presence of an antioxidant rescued mitochondrial function and reduced formation of Aβ, demonstrating that the observed effects depended on ROS. Conversely, cells overproducing Aβ showed impairment of mitochondrial function such as comprised mitochondrial respiration, strongly altered morphology, and reduced intracellular mobility of mitochondria. Again, the capability of these cells to generate Aβ was partly reduced by an antioxidant, indicating that Aβ formation was also ROS dependent. Moreover, mice with a genetic defect in complex I, or AD mice treated with a complex I inhibitor, showed enhanced Aβ levels in vivo.We show for the first time that mitochondrion-derived ROS are sufficient to trigger Aβ production in vitro and in vivo.Several lines of evidence show that mitochondrion-derived ROS result in enhanced amyloidogenic amyloid precursor protein processing, and that Aβ itself leads to mitochondrial dysfunction and increased ROS levels. We propose that starting from mitochondrial dysfunction a vicious cycle is triggered that contributes to the pathogenesis of sporadic AD.
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000136490 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000136490 650_7 $$2NLM Chemicals$$aReactive Oxygen Species
000136490 650_7 $$003L9OT429T$$2NLM Chemicals$$aRotenone
000136490 650_7 $$011118-72-2$$2NLM Chemicals$$aantimycin
000136490 650_7 $$0642-15-9$$2NLM Chemicals$$aAntimycin A
000136490 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000136490 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000136490 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000136490 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000136490 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000136490 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000136490 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000136490 650_2 $$2MeSH$$aAnimals
000136490 650_2 $$2MeSH$$aAntimycin A: analogs & derivatives
000136490 650_2 $$2MeSH$$aAntimycin A: pharmacology
000136490 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000136490 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism
000136490 650_2 $$2MeSH$$aCell Line
000136490 650_2 $$2MeSH$$aEnzyme-Linked Immunosorbent Assay
000136490 650_2 $$2MeSH$$aFlow Cytometry
000136490 650_2 $$2MeSH$$aHumans
000136490 650_2 $$2MeSH$$aMice
000136490 650_2 $$2MeSH$$aMice, Mutant Strains
000136490 650_2 $$2MeSH$$aMicroscopy, Confocal
000136490 650_2 $$2MeSH$$aMitochondria: drug effects
000136490 650_2 $$2MeSH$$aMitochondria: metabolism
000136490 650_2 $$2MeSH$$aReactive Oxygen Species: metabolism
000136490 650_2 $$2MeSH$$aRotenone: pharmacology
000136490 7001_ $$0P:(DE-HGF)0$$aSchütt, Tanja$$b1
000136490 7001_ $$0P:(DE-HGF)0$$aKurz, Christopher$$b2
000136490 7001_ $$0P:(DE-HGF)0$$aEckert, Schamim H$$b3
000136490 7001_ $$0P:(DE-HGF)0$$aSchiller, Carola$$b4
000136490 7001_ $$0P:(DE-HGF)0$$aOcchipinti, Angelo$$b5
000136490 7001_ $$0P:(DE-HGF)0$$aMai, Sören$$b6
000136490 7001_ $$0P:(DE-HGF)0$$aJendrach, Marina$$b7
000136490 7001_ $$0P:(DE-HGF)0$$aEckert, Gunter P$$b8
000136490 7001_ $$0P:(DE-HGF)0$$aKruse, Shane E$$b9
000136490 7001_ $$0P:(DE-HGF)0$$aPalmiter, Richard D$$b10
000136490 7001_ $$0P:(DE-HGF)0$$aBrandt, Ulrich$$b11
000136490 7001_ $$0P:(DE-HGF)0$$aDröse, Stephan$$b12
000136490 7001_ $$0P:(DE-HGF)0$$aWittig, Ilka$$b13
000136490 7001_ $$0P:(DE-2719)9000433$$aWillem, Michael$$b14$$udzne
000136490 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b15$$udzne
000136490 7001_ $$0P:(DE-HGF)0$$aReichert, Andreas S$$b16
000136490 7001_ $$0P:(DE-HGF)0$$aMüller, Walter E$$b17
000136490 77318 $$2Crossref$$3journal-article$$a10.1089/ars.2011.4173$$b : Mary Ann Liebert Inc, 2012-06-15$$n12$$p1421-1433$$tAntioxidants & Redox Signaling$$v16$$x1523-0864$$y2012
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