title: Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids.
abstract: Although oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative diseases such as Alzheimer's disease (AD), it is not fully understood how mitochondrial oxidative stress may induce neuronal death. We used mitochondrial transgenic neuronal cell cybrid models of sporadic AD (SAD) to investigate the effects of endogenously generated reactive oxygen species (ROS) on viability and cell death mechanisms. Compared to control (CTL) cybrids, SAD cybrids have increased accumulation of oxidative stress markers and increased apoptosis that is blocked by N-acetylcysteine (NAC) and zVAD.fmk. SAD cybrids also have increased basal activation of the MAPKs, Akt, and NF-kappa B. NF-kappa B activation and cybrid viability are enhanced by NAC. Inhibiting the activity of the PI3K pathway or NF-kappa B aggravates neuronal death. Exposure of CTL cybrids to H2O2 decreased viability and activated in a NAC-sensitive manner, the same intracellular signaling pathways active under basal conditions in SAD cybrids.
authors.affiliation: Center for the Study of Neurodegenerative Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. Onyango@virginia.edu
authors.forename: Isaac G
authors.initials: IG
authors.lastname: Onyango
authors.forename: James P
authors.initials: JP
authors.lastname: Bennett
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Tuttle
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016877:Oxidants