title: Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway.
abstract: Recent data have revealed that soluble oligomeric amyloid-beta peptide (Abeta) may be the proximate effectors of neuronal injuries and death in Alzheimer's disease (AD) by unknown mechanisms. Consistently, we recently demonstrated the critical role of a redox-sensitive cytosolic calcium-dependent phospholipase A2 (cPLA2)-arachidonic acid (AA) pathway in Abeta oligomer-induced cell death. According to the involvement of oxidative stress and polyunsaturated fatty acids like AA in the regulation of sphingomyelinase (SMase) activity, the present study underlines the role of SMases in soluble Abeta-induced apoptosis. Soluble Abeta oligomers induced the activation of both neutral and acidic SMases, as demonstrated by the direct measurement of their enzymatic activities, by the inhibitory effects of both specific neutral and acidic SMase inhibitors, and by gene knockdown using antisense oligonucleotides. Furthermore, soluble Abeta-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA2-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble Abeta oligomer-induced cell death and apoptosis by inhibiting soluble Abeta-induced activation of acidic sphingomyelinase. These results suggest that Abeta oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA2-AA pathway.
authors.affiliation: JE 2482 Lipidomix, INPL, Laboratoire de Médecine et Thérapeutique Moléculaire, 15 rue du Bois de la Champelle, F-54505 Vandoeuvre-lès-Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Malaplate-Armand
authors.forename: Sabrina
authors.initials: S
authors.lastname: Florent-Béchard
authors.forename: Ihsen
authors.initials: I
authors.lastname: Youssef
authors.forename: Violette
authors.initials: V
authors.lastname: Koziel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Sponne
authors.forename: Badreddine
authors.initials: B
authors.lastname: Kriem
authors.forename: Brigitte
authors.initials: B
authors.lastname: Leininger-Muller
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Olivier
authors.forename: Thierry
authors.initials: T
authors.lastname: Oster
authors.forename: Thierry
authors.initials: T
authors.lastname: Pillot
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016718:Arachidonic Acid / Q000494:pharmacology; D002518:Ceramides / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008246:Lysophospholipids; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016376:Oligonucleotides, Antisense; D010084:Oxidation-Reduction; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D016229:Amyloid beta-Peptides; D002518:Ceramides; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; C060506:sphingosine 1-phosphate; D016718:Arachidonic Acid; D010741:Phospholipases A; D054467:Phospholipases A2; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine