Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway.
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.
Malaplate-Armand
Catherine
C
JE 2482 Lipidomix, INPL, Laboratoire de Médecine et Thérapeutique Moléculaire, 15 rue du Bois de la Champelle, F-54505 Vandoeuvre-lès-Nancy, France.
Florent-Béchard
Sabrina
S
Youssef
Ihsen
I
Koziel
Violette
V
Sponne
Isabelle
I
Kriem
Badreddine
B
Leininger-Muller
Brigitte
B
Olivier
Jean-Luc
JL
Oster
Thierry
T
Pillot
Thierry
T
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
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