title: Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2 in cortical neurons.
abstract: Increase in oxidative stress has been postulated to play an important role in the pathogenesis of a number of neurodegenerative diseases including Alzheimer's disease. There is evidence for involvement of amyloid-beta peptide (Abeta) in mediating the oxidative damage to neurons. Despite yet unknown mechanism, Abeta appears to exert action on the ionotropic glutamate receptors, especially the N-methyl-D-aspartic acid (NMDA) receptor subtypes. In this study, we showed that NMDA and oligomeric Abeta(1-42) could induce reactive oxygen species (ROS) production from cortical neurons through activation of NADPH oxidase. ROS derived from NADPH oxidase led to activation of extracellular signal-regulated kinase 1/2, phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), and arachidonic acid (AA) release. In addition, Abeta(1-42)-induced AA release was inhibited by d(-)-2-amino-5-phosphonopentanoic acid and memantine, two different NMDA receptor antagonists, suggesting action of Abeta through the NMDA receptor. Besides serving as a precursor for eicosanoids, AA is also regarded as a retrograde messenger and plays a role in modulating synaptic plasticity. Other phospholipase A(2) products such as lysophospholipids can perturb membrane phospholipids. These results suggest an oxidative-degradative mechanism for oligomeric Abeta(1-42) to induce ROS production and stimulate AA release through the NMDA receptors. This novel mechanism may contribute to the oxidative stress hypothesis and synaptic failure that underline the pathogenesis of Alzheimer's disease.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Phullara B
authors.initials: PB
authors.lastname: Shelat
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Chalimoniuk
authors.forename: Jing-Hung
authors.initials: JH
authors.lastname: Wang
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Strosznajder
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Sun
authors.forename: Agnes
authors.initials: A
authors.lastname: Simonyi
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D016202:N-Methylaspartate / Q000633:toxicity*; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000633:toxicity*; D054510:Phospholipases A2, Cytosolic / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D016718:Arachidonic Acid; D016202:N-Methylaspartate; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D054510:Phospholipases A2, Cytosolic