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.

Fig. 1

Aβ oligomers stimulate oxidative/nitrosative pathways involving NMDA receptor, nNOS and NADPH oxidase leading to production of ROS and activation of cPLA2. cPLA2 has multiple actions; besides the release of AA and synthesis of eicosanoids, it can also produce DHA and lysoPL. These products have been shown to disturb mitochondrial function and modulate ROS production by NADPH oxidase. Dotted arrows are pathways not yet clarified. Note that besides the NO/cGMP/PKG pathway, many proteins in these pathways can undergo post-translational modifications through S-nitrosylation.