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Alzheimer's disease (AD) is a disorder of aging that is characterized by progressive loss of cognitive functioning, eventually culminating in complete dementia. Many lines of evidence, i.e., epidemiological, pathological and biochemical, suggest inflammatory processes play a role in neurodegenerative disease processes responsible for AD. Recent reports suggest that patients who chronically take anti-inflammatory drugs to treat the symptoms of inflammatory diseases, such as rheumatoid arthritis, have a reduced risk of developing AD. The inflammation found in the brains of AD patients is characterized by activated microglia, and astrocytes in brain regions that demonstrate extensive neuronal degeneration. In addition, the activated glia are closely associated with amyloid plaques and may contribute to their formation. Various molecules involved in inflammatory reactions, including cytokines, complement, arachidonic acid and prostaglandins are found to be elevated in the brain and CSF of AD patients. These molecules may also contribute to the evolution of the pathology in this disorder. The purpose of the first study was to determine if inflammatory processes are toxic to neurons. The results will show that both acute injections and chronic infusions of the proinflammagen lipopolysaccharide into the basal forebrain of rats was toxic to cholinergic cells. Chronic infusions of LPS decreased the level of activity of the acetylcholine synthetic enzyme choline acetyltransferase (ChAT). In addition, these infusions decreased the number of neurons that demonstrated immunoreactivity for this enzyme. Furthermore, low dose, long-term infusions of LPS produced a greater decline in ChAT activity than a single injection of high dose LPS. These results suggest that the toxic effects of neuroinflammation are more time-dependent than dose-dependent and support the hypothesis that long-term inflammatory processes can impair cholinergic neuronal function. The purpose of the second study was to examine the mechanism by which the chronic LPS infusions were neurotoxic to cholinergic neurons within the basal forebrain of young rats. This study investigated the hypothesis that increased activity of glutamate and prostaglandin neurons might underlie the toxic actions of chronic inflammation induced by LPS. First, this study investigated whether chronic administration of a noncompetitive N-methyl-D-aspartate (NMDA) sensitive receptor antagonist, memantine, could provide neuroprotection for forebrain cholinergic neurons. Second, this study also investigated whether a cyclooxygenase-2 (COX2)/lipoxygenase inhibitor, CI987, could provide significant neuroprotection from the cytotoxic effects of LPS-induced neuroinflammation. Daily peripheral administration of memantine (s.c.) or CI987 (s.c.) significantly attenuated the cytotoxic effects of the chronic inflammatory processes upon cholinergic cells within the basal forebrain. However, only CI987 attenuated the neuroinflammation produced by LPS and the subsequent changes in microglial activation. These results indicate that the cytotoxic effects of chronic neuroinflammation may involve prostanoid synthesis and may operate through NMDA receptors, and that the effects of prostaglandins occur upstream to NMDA receptor activation.