Cytosolic phospholipase A2α upregulation mediates apoptotic neuronal death induced by aggregated amyloid-β peptide 1-42

Chen Sagy-Bross, Nurit Hadad, Rachel Levy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Increased cytosolic phospholipase A2α (cPLA 2α) immunoreactivity and transcript were observed in Alzheimer's disease (AD) brain associated with amyloid deposits. Thus, the present study examined whether cPLA2α upregulation participate in cortical neuron damage induced by aggregated Aβ1-42 and determined its role in the signaling events leading to damage, using an antisense technology. Exposure of primary cortical neurons to 1 μM aggregated Aβ1-42 for 24 h induced up-regulation and activation of cPLA2α 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 cPLA2α up-regulation and activity in the presence of antisense against cPLA 2α (AS). cPLA2α was rapidly activated upon addition of aggregated Aβ1-42, 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 Aβ1-42 exposure was not affected by the presence of AS, but superoxide production was reduced, probably due to NOX2 inhibition. cPLA2α 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 2α activity plays a crucial role in the signaling cascade leading to apoptotic neuronal death by aggregated Aβ1-42 probably via activation of N-SMase, ceramide production and caspases-3 and -8.

Original languageEnglish
Pages (from-to)541-550
Number of pages10
JournalNeurochemistry International
Volume63
Issue number6
DOIs
StatePublished - 18 Oct 2013

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Arachidonic acid
  • Caspases
  • Cortical neurons
  • Cytosolic phospholipase Aα
  • NADPH oxidase

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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