title: Integrating cytosolic phospholipase A₂ with oxidative/nitrosative signaling pathways in neurons: a novel therapeutic strategy for AD.
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 A(2) (PLA(2)) 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 PLA(2) (cPLA(2)) and neuronal excitation due to stimulation of ionotropic glutamate receptors and toxic Aβ peptides. The requirements for Ca(2+) 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 cPLA(2) in serving multiple functions to neurons and glial cells under abnormal physiological and pathological conditions. Therefore, understanding mechanisms for cPLA(2) in the oxidative and nitrosative pathways in neurons will allow the development of novel therapeutic targets to mitigate the detrimental effects of AD.
authors.affiliation: Department of Biochemistry, University of Missouri, 117 Schweitzer Hall, Columbia, MO 65211, USA. sung@missouri.edu
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: He
authors.forename: Dennis Y
authors.initials: DY
authors.lastname: Chuang
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.forename: Zezong
authors.initials: Z
authors.lastname: Gu
authors.forename: Agnes
authors.initials: A
authors.lastname: Simonyi
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Sun
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D054510:Phospholipases A2, Cytosolic / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D054510:Phospholipases A2, Cytosolic