Phospholipase A2 (PLA2) is the key enzyme that initiates the arachidonic acid cascade, which leads to the generation of multiple eicosanoid products. Many of these products are believed to play an important role in the inflammatory process. Activation of PLA2 is observed under pathological conditions where inflammation is present. Cytosolic PLA2 (cPLA2) is activated by very low levels of calcium and is thought to control receptor-mediated eicosanoid production and to participate in intracellular signal transduction processes. In view of the presence of numerous inflammatory mediators and acute phase proteins in the Alzheimer's disease (AD) brain, localization of cPLA2 in AD brain was evaluated and compared to that observed in nonneurologically diseased controls. In this study, a monoclonal antibody raised against cPLA2 was used to immunostain tissue sections of human cerebral cortex. Five AD cases and six neurologically normal cases were evaluated in the occipital cortex and the cerebellum. Two of the AD cases were also examined in other cortical regions. Granular-like staining with anti-cPLA2 was found to be associated with astrocytes in the cortex of both control and AD cases. Colocalization with GFAP confirmed that cPLA2 immunoreactivity is associated almost exclusively with protoplasmic astrocytes. Staining was abolished when sections were labeled with antibody that had been preadsorbed with purified cPLA2. In AD brain, cPLA2 immunoreactive astrocytes were greater in number and more intensely stained than those in control cases. cPLA2 immunoreactivity was virtually absent in the cerebelium of AD and control cases, despite the presence in this region of diffuse amyloid in two AD cases and amyloid angiopathy in a third case. In the cortex, cPLA2 immunoreactive astrocytes were detected in regions that contained numerous A beta deposits. The finding of elevated levels of cPLA2 immunoreactivity in AD brain supports the hypothesis that there is an active inflammatory process occurring in AD.