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Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway.
- Source :
-
Neurobiology of disease [Neurobiol Dis] 2006 Jul; Vol. 23 (1), pp. 178-89. Date of Electronic Publication: 2006 Apr 19. - Publication Year :
- 2006
-
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.
- Subjects :
- Animals
Apoptosis drug effects
Arachidonic Acid pharmacology
Enzyme Activation drug effects
Enzyme Activation physiology
Enzyme Inhibitors pharmacology
Lysophospholipids
Neurons drug effects
Neurons metabolism
Oligonucleotides, Antisense
Oxidation-Reduction
Phospholipases A2
Rats
Reactive Oxygen Species metabolism
Signal Transduction physiology
Sphingosine analogs & derivatives
Amyloid beta-Peptides metabolism
Apoptosis physiology
Ceramides metabolism
Neurons pathology
Phospholipases A metabolism
Sphingomyelin Phosphodiesterase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0969-9961
- Volume :
- 23
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 16626961
- Full Text :
- https://doi.org/10.1016/j.nbd.2006.02.010