Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway

Recent data have revealed that soluble oligomeric amyloid-beta peptide (A beta) 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 A(2) (cPLA(2))-arachidonic acid (AA) pathway in A 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 A beta-induced apoptosis. Soluble A beta 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 A beta-mediated activation of SMases and subsequent cell death were found to be inhibited by antioxidant molecules and a cPLA(2)-specific inhibitor or antisense oligonucleotide. We also demonstrate that sphingosine-1-phosphate is a potent neuroprotective factor against soluble A oligomer-induced cell death and apoptosis by inhibiting soluble A beta-induced activation of acidic sphingomyelinase. These results suggest that A beta oligomers induce neuronal death by activating neutral and acidic SMases in a redox-sensitive cPLA(2)-AA pathway. (c) 2006 Elsevier Inc. All rights reserved.