The role of cytosolic phospholipase A(2)alpha in an amyloid precursor protein induction by amyloid beta(1-42): implication for neurodegeneration

Amyloid-beta pepticies generated by proteolysis of the beta-amyloid precursor protein (APP) play an important role in the pathogenesis of Alzheimer's disease. The present study aimed to determine whether cytosolic phospholipase A(2)alpha (cPLA(2)alpha) plays a role in elevated APP protein expression induced by aggregated amyloid-beta(1-42) (A beta) in cortical neurons and to elucidate its specific role in signal events leading to APP induction. Elevated cPLA(2)alpha 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 A beta for 24 h and in cortical neuron of human amyloid-beta(1-42) brain infused mice. Prevention of cPLA(2)alpha up-regulation and its activity by oligonucleotide antisense against cPLA(2)alpha (AS) prevented the elevation of APP protein in cortical neuronal cultures and in mouse neuronal cortex. To determine the role of cPLA(2)alpha in the signals leading to APP induction, increased cPLA(2)alpha expression and activity induced by A beta was prevented by means AS in neuronal cortical cultures. Under these conditions, the elevated cyclooxygenase-2 and the production of prostaglandin E-2 (PGE(2)) were prevented. Addition of PGE(2) 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 A beta. Inhibition of elevated cPLA(2)alpha 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 A beta which coincided with cPLA(2)alpha dependent activation of CREB in the cortex of A beta brain infused mice. Our results show that accumulation of Afi induced elevation of APP protein expression mediated by cPLA(2)alpha, PGE(2) release, and CREB activation via protein kinase A pathway.