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Integrating Cytosolic Phospholipase A2 with Oxidative/Nitrosative Signaling Pathways in Neurons: A Novel Therapeutic Strategy for AD

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Abstract

The pathophysiology of Alzheimer's disease (AD) is comprised of complex metabolic abnormalities in different cell types in the brain. To date, there are not yet effective drugs that can completely inhibit the pathophysiological event, and efforts have been devoted to prevent or minimize the progression of this disease. Much attention has focused on studies to understand aberrant functions of the ionotropic glutamate receptors, perturbation of calcium homeostasis, and toxic effects of oligomeric amyloid beta peptides (Aβ) which results in production of reactive oxygen and nitrogen species and signaling pathways, leading to mitochondrial dysfunction and synaptic impairments. Aberrant phospholipase A2 (PLA2) activity has been implicated to play a role in the pathogenesis of many neurodegenerative diseases, including AD. However, mechanisms for their modes of action and their roles in the oxidative and nitrosative signaling pathways have not been firmly established. In this article, we review recent studies providing a metabolic link between cytosolic PLA2 (cPLA2) and neuronal excitation due to stimulation of ionotropic glutamate receptors and toxic Aβ peptides. The requirements for Ca2+ binding together with its posttranslational modifications by protein kinases and possible by the redox-based S-nitrosylation, provide strong support for a dynamic role of cPLA2 in serving multiple functions to neurons and glial cells under abnormal physiological and pathological conditions. Therefore, understanding mechanisms for cPLA2 in the oxidative and nitrosative pathways in neurons will allow the development of novel therapeutic targets to mitigate the detrimental effects of AD.

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Acknowledgments

This study was supported by NIH grants P02 AG018357 NIA and 1P50 AT006273 from NCCAM.

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Authors and Affiliations

  1. Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO, 65211, USA

    Grace Y. Sun, Yan He, Dennis Y. Chuang & Agnes Simonyi

  2. Department of Biological Engineering, University of Missouri, Columbia, MO, 65211, USA

    James C. Lee

  3. Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO, 65211, USA

    Zezong Gu & Albert Y. Sun

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  1. Grace Y. Sun
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  2. Yan He
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  3. Dennis Y. Chuang
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Correspondence to Grace Y. Sun.

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Sun, G.Y., He, Y., Chuang, D.Y. et al. Integrating Cytosolic Phospholipase A2 with Oxidative/Nitrosative Signaling Pathways in Neurons: A Novel Therapeutic Strategy for AD. Mol Neurobiol 46, 85–95 (2012). https://doi.org/10.1007/s12035-012-8261-1

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