Regulatory role of cytosolic phospholipase A2α in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Aβ1–42 in microglia
✍ Scribed by I. Szaingurten-Solodkin; N. Hadad; R. Levy
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 532 KB
- Volume
- 57
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
Abstract
In Alzheimer's disease, extracellular deposits of amyloid β~1–42~ (Aβ~1–42~) may induce activation of microglial cells by releasing proinflammatory factors that contribute to the neurodegeneration process. Since the activation of cytosolic phospholipase A~2~α (cPLA~2~α) has been reported in inflammatory conditions, its role in primary rat microglial cell activated by aggregated Aβ~1–42~ was elucidated. The results of the present study show that activation of microglia by 5 μM aggregated Aβ~1–42~ (as evident by the amoeboid morphology and increased CD68 immunofluorescence reactivity) caused an immediate activation of cPLA~2~α, measured by its phosphorylated form and its specific activity, followed by a gradual elevation of its expression and activity during 24 h. Inhibition of cPLA~2~α expression and activity by the presence of 1 μM specific antisense resulted in a significant decrease in NADPH oxidase activity that releases superoxides, PGE~2~ formation, iNOS expression, and NO production, indicating a major role for cPLA~2~α in the regulation of these inflammatory processes. NADPH oxidase activity, which is under cPLA~2~α regulation, was found to upregulate cPLA~2~α and COX‐2 protein expression through the redox‐sensitive NFκB activation as evident by its phosphorylation on Ser‐536, resulting in increased PGE~2~ formation. The secreted PGE~2~ induced the synthesis of iNOS and the production of NO through the PKA‐CREB pathway. Taken together, our results suggest that the response of cPLA~2~α to aggregated Aβ~1–42~ is probably a key player in the oxidative stress present in AD, regulating potent oxidative agents: the production of superoxides by NADPH oxidase and NO formation by iNOS. © 2009 Wiley‐Liss, Inc.