- Increased cytosolic phospholipase A 2 α (cPLA 2 α) immunoreactivity and transcript were observed in Alzheimer’s disease (AD) brain associated with amyloid deposits. Thus, the present study examined whether cPLA 2 α upregulation participate in cortical neuron damage induced by aggregated Aβ 1–42 and determined its role in the signaling events leading to damage, using an antisense technology. Exposure of primary cortical neurons to 1 μM aggregated Aβ 1–42 for 24 h induced up-regulation and activation of cPLA 2 α and apoptotic cell death of about 30% as detected by: cell count, MTT reduction, caspases-3 and -8 activation, DAPI and TUNEL staining, that were prevented by inhibition of cPLA 2 α up-regulation and activity in the presence of antisense against cPLA 2 α (AS). cPLA 2 α was rapidly activated upon addition of aggregated Aβ 1–42 , as determined by its phosphorylated form on serine 505, and this activity was dependent on NADPH oxidase activity. NOX2- and NOX4-NADPH oxidase upregulation at 24 h of aggregated Aβ 1–42 exposure was not affected by the presence of AS, but superoxide production was reduced, probably due to NOX2 inhibition. cPLA 2 α upregulation led to activation of neutral sphingomyelinase (N-SMase) as its activity was inhibited in the presence of AS, and could be restored by addition of arachidonic acid. Addition of ceramide analog induced caspase-8 activation leading to caspase-3 activation and apoptotic neuronal death. In conclusion, our results suggest that cPLA 2 α activity plays a crucial role in the signaling cascade leading to apoptotic neuronal death by aggregated Aβ 1–42 probably via activation of N-SMase, ceramide production and caspases-3 and -8.