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- Title
Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A<sub>2</sub> in cortical neurons.
- Authors
Shelat, Phullara B.; Chalimoniuk, Malgorzata; Wang, Jing-Hung; Strosznajder, Joanna B.; Lee, James C.; Sun, Albert Y.; Simonyi, Agnes; Sun, Grace Y.
- 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-β peptide (Aβ) in mediating the oxidative damage to neurons. Despite yet unknown mechanism, Aβ 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 Aβ1–42 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 A2α (cPLA2α), and arachidonic acid (AA) release. In addition, Aβ1–42-induced AA release was inhibited byd(−)-2-amino-5-phosphonopentanoic acid and memantine, two different NMDA receptor antagonists, suggesting action of Aβ 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 A2 products such as lysophospholipids can perturb membrane phospholipids. These results suggest an oxidative-degradative mechanism for oligomeric Aβ1–42 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
ARACHIDONIC acid; NEUROPLASTICITY; CHEMICAL reactions; METHYL aspartate; NEURODEGENERATION
- Publication
Journal of Neurochemistry, 2008, Vol 106, Issue 1, p45
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2008.05347.x