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Amyloid beta peptide and NMDA induce ROS from NADPH oxidase and AA release from cytosolic phospholipase A 2 in cortical neurons
Author(s) -
Shelat Phullara B.,
Chalimoniuk Malgorzata,
Wang JingHung,
Strosznajder Joanna B.,
Lee James C.,
Sun Albert Y.,
Simonyi Agnes,
Sun Grace Y.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05347.x
Subject(s) - nadph oxidase , nmda receptor , phospholipase a2 , arachidonic acid , reactive oxygen species , oxidative stress , biology , biochemistry , microbiology and biotechnology , chemistry , receptor , enzyme
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 Aβ 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 α (cPLA 2 α), and arachidonic acid (AA) release. In addition, Aβ 1–42 ‐induced AA release was inhibited by d (−)‐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 A 2 products such as lysophospholipids can perturb membrane phospholipids. These results suggest an oxidative‐degradative mechanism for oligomeric Aβ 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.