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Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A2in cortical neurons
- Source :
- Journal of Neurochemistry. 106:45-55
- Publication Year :
- 2008
- Publisher :
- Wiley, 2008.
-
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.
- Subjects :
- N-Methylaspartate
Amyloid beta
Phospholipases A2, Cytosolic
Receptors, N-Methyl-D-Aspartate
Biochemistry
Rats, Sprague-Dawley
Cellular and Molecular Neuroscience
Phospholipase A2
Alzheimer Disease
Excitatory Amino Acid Agonists
medicine
Animals
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Cells, Cultured
Cerebral Cortex
Neurons
Phospholipase A
Amyloid beta-Peptides
Arachidonic Acid
NADPH oxidase
biology
Glutamate receptor
Memantine
NADPH Oxidases
Peptide Fragments
Rats
Oxidative Stress
Synaptic plasticity
biology.protein
NMDA receptor
Reactive Oxygen Species
Excitatory Amino Acid Antagonists
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 14714159 and 00223042
- Volume :
- 106
- Database :
- OpenAIRE
- Journal :
- Journal of Neurochemistry
- Accession number :
- edsair.doi.dedup.....7e21166434d922cf7859b137b7686c02