- Amyloid-β peptides generated by proteolysis of the β-amyloid precursor protein (APP) play an important role in the pathogenesis of Alzheimer's disease. The present study aimed to determine whether cytosolic phospholipase A2α (cPLA2α) plays a role in elevated APP protein expression induced by aggregated amyloid-β1-42 (Aβ) in cortical neurons and to elucidate its specific role in signal events leading to APP induction. Elevated cPLA2α and its activity determined by phosphorylation on serine 505 as well as elevated APP protein expression, were detected in primary rat cortical neuronal cultures exposed to Aβ for 24 h and in cortical neuron of human amyloid-β1-42 brain infused mice. Prevention of cPLA2α up-regulation and its activity by oligonucleotide antisense against cPLA2α (AS) prevented the elevation of APP protein in cortical neuronal cultures and in mouse neuronal cortex. To determine the role of cPLA2α in the signals leading to APP induction, increased cPLA2α expression and activity induced by Aβ was prevented by means of AS in neuronal cortical cultures. Under these conditions, the elevated cyclooxygenase-2 and the production of prostaglandin E2 (PGE2) were prevented. Addition of PGE2 or cyclic AMP analogue (dbcAMP) to neuronal cultures significantly increased the expression of APP protein, while the presence protein kinase A inhibitor (H-89) attenuated the elevation of APP induced by Aβ. Inhibition of elevated cPLA2α by AS prevented the activation of cAMP response element binding protein (CREB) as detected by its phosphorylated form, its translocation to the nucleus and its DNA binding induced by Aβ which coincided with cPLA2α dependent activation of CREB in the cortex of Aβ brain infused mice. Our results show that accumulation of Aβ induced elevation of APP protein expression mediated by cPLA2α, PGE2 release, and CREB activation via protein kinase A pathway. Amyloid-β (Aβ) peptides generated by proteolysis of the β-amyloid precursor protein (APP) play an important role in the pathogenesis of Alzheimer's disease. We show here that cytosolic phospholipase A2α has a profound role in APP over-expression induced by Aβ both in vitro and in vivo via PGE2 production and CREB activation through cAMP/PKA pathway and thus may serve as a therapeutic target. AS, oligonucleotide antisense against cPLA2α; cAMP, cyclic adenosine monophosphate; COX-2, cyclooxygenase-2; cPLA2α, cytosolic phospholipase A2α; CREB, cAMP response element binding protein; EP, E-prostanoid receptors; H89, a PKA inhibitor; PGE2, prostaglandin E2; PKA, protein kinase A.