title: Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis.
abstract: Current evidence suggests that amyloid beta peptides (Abeta) may play a major role in the pathogenesis of Alzheimer's disease by eliciting oxidative stress and neuronal apoptosis. In this study we have used differentiated SK-N-BE neurons to investigate molecular mechanisms and regulatory pathways underlying apoptotic neuronal cell death elicited by Abeta(1-40) and Abeta(1-42) peptides as well as the relationships between apoptosis and oxidative stress. Abeta peptides, used at concentrations able to induce oxidative stress, elicit a classic type of neuronal apoptosis involving mitochondrial regulatory proteins and pathways (i.e. affecting Bax and Bcl-2 protein levels as well as release of cytochrome c in the cytosol), poly-ADP rybose polymerase cleavage and activation of caspase 3. This pattern of neuronal apoptosis, that is significantly prevented by alpha-tocopherol and N-acetylcysteine and completely abolished by specific inhibitors of stress-activated protein kinases (SAPK) such as JNKs and p38(MAPK), involved early elevation of p53 protein levels. Pretreatment of neurons with alpha-pifithrin, a specific p53 inhibitor, resulted in a 50-60% prevention of Abeta induced apoptosis. These results suggest that oxidative stress - mediated neuronal apoptosis induced by amyloid beta operates by eliciting a SAPK-dependent multiple regulation of pro-apoptotic mitochondrial pathways involving both p53 and bcl-2.
authors.affiliation: Department of Experimental Medicine and Oncology, General Pathology Section, University of Turin, Corso Raffaello 30, 10125 Turin, Italy. elena.tamagno@unito.it
authors.forename: Elena
authors.initials: E
authors.lastname: Tamagno
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Michela
authors.initials: M
authors.lastname: Guglielmotto
authors.forename: Gianni
authors.initials: G
authors.lastname: Santoro
authors.forename: Paola
authors.initials: P
authors.lastname: Bardini
authors.forename: Laura
authors.initials: L
authors.lastname: Marra
authors.forename: Massimo
authors.initials: M
authors.lastname: Tabaton
authors.forename: Oliviero
authors.initials: O
authors.lastname: Danni
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008928:Mitochondria / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology; D051028:bcl-2-Associated X Protein; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016229:Amyloid beta-Peptides; C494826:BAX protein, human; D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; D014050:Toluene; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C121565:pifithrin; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D024502:alpha-Tocopherol; D000111:Acetylcysteine