There is strong support for the hypothesis that folding of p-amyloid (AP) peptide into a neurotoxic, oligomeric form is associated with increased oxidative stress that constitutes early events in the neuronal impairment and glial cell-mediated inflammation seen in Alzheimer's disease (AD). Phospholipases A2 (PLA2), including cytosolic cPLA2 and inflammatory secretory sPLA2-IIA, are important enzymes for the production of lipid mediators and the maintenance of membrane integrity. Although these enzymes have been implicated in other diseases, their roles in the pathogenesis of AD have not been explored sufficiently. Our recent studies have obtained novel data indicating that oligomeric Ap42 treatment of neurons enhances ROS production through NADPH oxidase and increases cPLA2 activity through intracellular kinase activation, resulting in membrane peroxidation and alterations in membrane protein function. Other new data show that sPLA2-IIA mRNA and protein expression are elevated in AD brain compared to age-matched controls. The overall goal of this project is to understand mechanisms whereby A|3, NADPH oxidase, cPLA2 and sPLA2-IIA collectively contribute to impairment of neuronal function and induction of glial-cell mediated inflammation, using accepted and novel in vitro and in vivo models of AD.
Aim 1 tests the hypothesis that Ap-induced cPLA2 and NADPH oxidase activation in neurons serves to modulate N-methyl-D-aspartic acid (NMDA) receptor function and induce neuronal apoptosis.
Aim 2 investigates the significance and relevance to AD pathogenesis of the novel preliminary data indicating that sPLA2-IIA is up-regulated in AD and tests the hypothesis that increases in sPLA2-IIA expression caused by oligomeric Ap42 and NADPH oxidase-dependent ROS generation modulate inflammatory responses in glial cells and cause neuronal apoptosis. We will test the hypothesis that NADPH oxidase and cPLA2 up-regulate sPLA2-IIA expression and modulate inflammatory responses in glial cells, thus linking oxidative pathways to neuroinflammation. Proposed studies to evaluate novel roles for PLA2s in neuronal and glial cell functions associated with AD will evaluate responses in primary neurons and astrocytesfrom the TgCRNDS mouse model of AD, NT-2 cells over-expressing the Swedish/Indiana mutant of APP, human AD and non-demented (ND) brain tissue, and brain slices from transgenic mouse models, including TgCRNDS and TgCRNDS x sPLA2-IIA, and mice lacking cPLA2 and gp91phox, a NADPH oxidase subunit. Together, these studies will provide new information about the roles of neuronal cPLA2 in enhancing oxidative stress and impairing glutamatergic signaling in the early stages of AD, and the role of sPLA2-IIA in inflammatory responses in glial cells, information that we believe can lead to novel pharmacotherapies to retard disease progression.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Missouri-Columbia
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