Cytosolic phospholipase A₂mediates neuronal apoptosis induced by soluble oligomers of the amyloid‐β peptide

Abstract

Recent data have revealed that soluble oligomeric forms of amyloid peptide (Abeta) may be the proximate effectors of the neuronal injury and death occurring in Alzheimer's disease (AD). However, the molecular mechanisms associated with the neuronal cell death induced by the nonfibrillar Abeta remain to be elucidated. In this study, we investigated the role of the cytosolic Ca2+-dependent phospholipase A2 (cPLA2), and its associated metabolic pathway, i.e., the arachidonic acid (AA) cascade, in the apoptotic cell death induced by soluble oligomers of Abeta. The treatment of rat cortical neurons with low concentrations of soluble Abeta(1-40) or Abeta(1-42) peptide resulted in an early calcium-dependent release of AA associated with a transient relocalization of cPLA2. Both cPLA2 antisense oligonucleotides and a selective inhibitor of cPLA2 activity abolished the release of AA from neurons and also protected cells against apoptosis induced by Abeta. Furthermore, inhibitors of the PKC, p38, and MEK/ERK pathways that are involved in cPLA2 phosphorylation and activation reduced Abeta-induced cell death. Finally, we demonstrate that inhibitors of cyclooxygenase-2 reduced the Abeta-induced cell death by 55%. Our studies suggest a novel neuronal response of soluble oligomers of Abeta, which occurs through a cPLA2 signaling cascade and an AA-dependent death pathway. This may prove to be crucial in AD processes and could provide important targets for drug development.

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

“…As expected from our previous reports Garcia et al, 2010;Kriem et al, 2005;Malaplate-Armand et al, 2006), the incubation of cortical neurons of WT mice with 1 or 5 M A␤ 42 oligomers for 24 hours resulted in a 40%-50% decrease in cell viability (Fig. 5A), whereas 1 M A␤ 42 induced a 5-fold increase in apoptotic nuclei number, as compared with untreated WT neurons (Fig.…”

“…We previously reported that soluble A␤ oligomers caused early calcium-dependent release of AA associated with a transient relocalization of cPLA 2 to the plasma membrane, suggesting that activation of cPLA 2 and subsequent release of AA are critical steps for soluble A␤ oligomermediated apoptosis in cortical neurons. We confirmed this hypothesis by using antisense oligonucleotides and pharmacological inhibitors of cPLA 2 that abolished AA release and protected neurons against A␤-induced apoptosis (Kriem et al, 2005). Furthermore, we demonstrated that activation of cPLA 2 by A␤ oligomers precedes that of sphingomyelinases (SMases) and subsequent production of ceramides associated with neuronal apoptosis .…”

“…Cells were treated with 1 or 5 M soluble oligomers of A␤ 42 for the indicated times or with 1 or 2 M of the cPLA 2 inhibitor methoxy arachidonyl fluorophosphonate (MAFP) for 24 hours. Two sets of cPLA 2 sense and antisense oligonucleotides were designed and used as previously described (Kriem et al, 2005).…”

“…Cell nuclei were visualized using 4,6-diamidino-2-phenylindole (DAPI) staining (Sponne et al, 2004). To evaluate the percentage of apoptotic cells, 10 independent fields of microscope were counted (approximately 400 cells) in 3 separate experiments with 3 determinations each (Kriem et al, 2005).…”

Development and Expression of Amyloid‐β Peptide 42 in Retinal Ganglion Cells in Rats

“…In vitro studies also showed that a high dose of Ab-42 induced neuronal degeneration and neurapophysis retraction (Pike et al, 1992;Dahlgren et al, 2002). Recent data indicates that neuronal injuries and death have been correlated with the status of Ab-42 (Sponne et al, 2004;Kriem et al, 2005). Despite there are studies suggesting the role of soluble Ab-42 in promoting the growth of neurapophysis and enhancing neuron survival in a short time, other researches has shown that soluble Ab-42 oligomers may be the proximate effectors of AD and that Ab-42 in soluble oligomeric status can induce neuronal death (Gong et al, 2003;Kim et al, 2003;Florent et al, 2006).…”