title: Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells.
abstract: Amyloid beta-protein (Abeta) aggregation produces an oxidative stress in neuronal cells that, in turn, may induce an amyloidogenic shift of neuronal metabolism. To investigate this hypothesis, we analyzed intra- and extracellular Abeta content in NT2 differentiated cells incubated with 4-hydroxy-2,3-nonenal (HNE), a major product of lipid peroxidation. In parallel, we evaluated protein kinase C (PKC) isoenzymes activity, a signaling system suspected to modulate amyloid precursor protein (APP) processing. Low HNE concentrations (0.1-1 microM) induced a 2-6 fold increase of intracellular Abeta production that was concomitant with selective activation of betaI and betaII PKC isoforms, without affecting either cell viability or APP full-length expression. Selective activation of the same PKC isoforms was observed following NT2 differentiation. Our findings suggest that PKC beta isoenzymes are part of cellular mechanisms that regulate production of the intracellular Abeta pool. Moreover, they indicate that lipid peroxidation fosters intracellular Abeta accumulation, creating a vicious neurodegenerative loop.
authors.affiliation: Department of Experimental Medicine, General Pathology Section, University of Bologna, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Paola
authors.forename: C
authors.initials: C
authors.lastname: Domenicotti
authors.forename: M
authors.initials: M
authors.lastname: Nitti
authors.forename: A
authors.initials: A
authors.lastname: Vitali
authors.forename: R
authors.initials: R
authors.lastname: Borghi
authors.forename: D
authors.initials: D
authors.lastname: Cottalasso
authors.forename: D
authors.initials: D
authors.lastname: Zaccheo
authors.forename: P
authors.initials: P
authors.lastname: Odetti
authors.forename: P
authors.initials: P
authors.lastname: Strocchi
authors.forename: U M
authors.initials: UM
authors.lastname: Marinari
authors.forename: M
authors.initials: M
authors.lastname: Tabaton
authors.forename: M A
authors.initials: MA
authors.lastname: Pronzato
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000378:metabolism*; D064546:Protein Kinase C beta; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D011493:Protein Kinase C; D064546:Protein Kinase C beta