title: Apoptotic neuronal cell death induced by the non-fibrillar amyloid-beta peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation.
abstract: In the present study, we have determined the nature and the kinetics of the cellular events triggered by the exposure of cells to non-fibrillar amyloid-beta peptide (A beta). When cortical neurons were treated with low concentrations of soluble A beta (1-40), an early reactive oxygen species (ROS)-dependent cytoskeleton disruption precedes caspase activation. Indeed, caspase activation and neuronal cell death were prevented by the microtubule-stabilizing drug taxol. A perturbation of the microtubule network was noticeable after being exposed to A beta for 1 h, as revealed by electron microscopy and immunocytochemistry. Microtubule disruption and neuronal cell death induced by A beta were inhibited in the presence of antioxidant molecules, such as probucol. These data highlight the critical role of ROS production in A beta-mediated cytoskeleton disruption and neuronal cell death. Finally, using FRAP (fluorescence recovery after photo bleaching) analysis, we observed a time-dependent biphasic modification of plasma membrane fluidity, as early as microtubule disorganization. Interestingly, molecules that inhibited neurotubule perturbation and cell death did not affect the membrane destabilizing properties of A beta, suggesting that the lipid phase of the plasma membrane might represent the earliest target for A beta. Altogether our results convey the idea that upon interaction with the plasma membrane, the non-fibrillar A beta induces a rapid ROS-dependent disorganization of the cytoskeleton, which results in apoptosis.
authors.affiliation: INSERM EMI 0014, Université de Nancy I, 54505 Vandoeuvre, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sponne
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fifre
authors.forename: Béatrice
authors.initials: B
authors.lastname: Drouet
authors.forename: Christophe
authors.initials: C
authors.lastname: Klein
authors.forename: Violette
authors.initials: V
authors.lastname: Koziel
authors.forename: Martine
authors.initials: M
authors.lastname: Pinçon-Raymond
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Olivier
authors.forename: Jean
authors.initials: J
authors.lastname: Chambaz
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure*; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); D020169:Caspases