Secretory phospholipase A2-IIA in Alzheimer's disease and inflammatory responses in astrocytes

Alzheimer’s disease (AD) is a progressive, fatal neurodegenerative disease and is the most common form of dementia. AD pathology includes neurofibrillary tangles, amyloid plaques, chronic inflammation, and oxidative stress. Secretory phospholipase A2-IIA (sPLA2-IIA) is an inflammatory protein known to have a role in the pathogenesis of multiple inflammatory diseases and is implicated in several neurodegenerative diseases. In AD, astrocytes become reactive and have increased expression of inflammatory cytokines such as IL-1! and TNF-#, and undergo increased oxidative stress. NADPH oxidase is one of the major enzymatic sources of reactive oxygen species in the central nervous system; activation of this enzyme may contribute to increased oxidative stress in cells of AD brains, including astrocytes. The expression and localization of sPLA2-IIA in human AD brains has not been studied in detail. In these studies, we show that sPLA2-IIA mRNA is up-regulated in AD brains (compared to nondemented elderly brains) and sPLA2-IIA immunoreactivity is increased in AD astrocytes. To further elucidate involvement of oxidative pathways in induction of sPLA2-IIA mRNA and protein by pro-inflammatory cytokines, we performed in vitro studies with immortalized astrocytes (DITNC). These studies demonstrated the involvement of PI-3 kinase and ERK1/2, but not p38 MAPK, in the cytokine-induced sPLA2-IIA expression