The role of cytosolic phospholipase A₂α in amyloid precursor protein induction by amyloid beta_1-42: Implication for neurodegeneration

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-β_1-42 (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-β_1-42 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.