Amyloid beta induces cPLA2 activation by an NADPH oxidase-dependent mechanism in neurons

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Alzheimer's disease (AD) is a neurodegenerative disorder affecting more than 20 million people worldwide. An increase in production of amyloid beta peptides (A[Beta]) and their aggregation to the oligomeric form is thought to contribute to neurotoxicity in the AD brain. cPLA2 is an enzyme responsible for hydrolysis of fatty acids in the sn-2 position of membrane phospholipids. Substantial attention has been paid to arachidonic acid (AA) because this lipid mediator is not only used for prostanoid synthesis but is also regarded as a retrograde transmitter. cPLA2 has been implicated in the pathogenesis of a number of neurodegenerative diseases including AD. Recent studies provided evidence for the production of reactive oxygen species (ROS) in association with glutamate excitotoxicity and involvement of NMDA receptors in A[Beta]-induced neurotoxicity. This study is focused on elucidating the role of NADPH oxidase, a superoxide producing enzyme, on the signaling pathway leading to cPLA2 activation and AA release in cortical neurons. Results show that A[Beta] and NMDA can produce ROS in neurons via NADPH oxidase and that this pool of ROS is important for ERK1/2 phosphorylation, cPLA2 phosphorylation and subsequent AA release. The study presented here identifies for the first time the importance of the ROS producing enzyme NADPH oxidase in the signaling pathway leading to A[Beta]-induced and NMDA receptor-mediated cPLA2 activation in neurons. This novel mechanism may contribute to a better understanding of the oxidative mechanism underlying the pathogenesis of AD.