title: Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gamma-secretase expression.
abstract: The pathogenesis of Alzheimer disease (AD) is complex and is certain to involve diverse etiological factors, but a central role has been strongly suggested for amyloid beta-protein (Abeta), based on genetic, biochemical and neurotoxicological evidence. In contrast with the well-documented effect of genetic mutations in Abeta overproduction, not much is known about the mechanisms involved in sporadic AD (SAD) which account for more than 95% of cases. Extensive data from patients and in vivo animal models indicate that oxidative stress is one of the cardinal factors most frequently associated with this neurodegenerative disease. The aim of the present study was to explore the effect of oxidative stress on the normally expressed wild-type amyloid precursor protein (APP) in human neuroblastoma cells, which represents a more physiological model of neuronal Abeta generation. Since H(2)O(2) is the main source of the highly reactive hydroxyl radical in the brain, and FeCl(2) can stimulate oxidative stress, including the formation of the hydroxyl radical from H(2)O(2), in the present work we studied the effect of these two pro-oxidant molecules on the levels and processing of human APP by alpha-, beta- and gamma-secretase, and the role of the stress-activated kinase c-jun N-terminal kinase (JNK). We provide evidence for a dual modulation of amyloid precursor protein metabolism in differentiated human neuroblastoma cells related with a down-regulation of alpha-secretase and up-regulation of gamma-secretase, and particularly of beta-secretase and also a JNK depending Abeta generation.
authors: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, DF, Mexico.
authors: Ricardo
authors: R
authors: Quiroz-Baez
authors: Emilio
authors: E
authors: Rojas
authors: Clorinda
authors: C
authors: Arias
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D002712:Chlorides; D004797:Enzyme-Linked Immunosorbent Assay; D005290:Ferric Compounds / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism; D007150:Immunohistochemistry; D048670:MAP Kinase Kinase 4 / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002712:Chlorides; D005290:Ferric Compounds; D016877:Oxidants; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases; C024555:ferric chloride