PROSTAGLANDINS AS PUTATIVE NEUROTOXINS IN ALZHEIMERS-DISEASE

Chronic inflammatory reactions in the brain appear to be one of the pr imary etiological factors in the pathogenesis of Alzheimer's disease ( AD). This is supported by the fact that the secretory products of infl ammatory reactions, which include cytokines, complement proteins, adhe sion molecules, and free radicals, are neurotoxic. We have recently re ported that prostaglandins (PGs), which are also released during infla mmatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma cells (NB) in culture, PGA(1) is more effective t han PGE(1). Similar observations were made in a primary culture of fet al rat hippocampal cells. Epidemiological and clinical studies on AD a lso support the involvement of PGs in neuronal degeneration, Thus, we propose a hypothesis that PGs are one of the major extracellular signa ls that initiate neuronal degeneration, which is mediated by intracell ular signals such as the beta-amyloid peptide (A beta) and ubiquitin, since the levels of these proteins are increased by PG treatment. We f urther suggest that adenosine 3', 5'-cyclic monophosphate (cAMP) is on e of the factors that regulate the levels of both A beta and ubiquitin in NE cells. Increases in the level of A beta in NE cells following a n elevation of intracellular cAMP levels appear to be due to an increa se in the rate of processing of the amyloid precursor protein (APP) ra ther than an increase in the expression of APP, The mechanisms underly ing A beta-induced neuronal degeneration have been under intense inves tigation, and several mechanisms of action have been proposed, We post ulate that PG-induced elevation of A beta may lead to an increased bin ding of A beta to the 20S proteasome, resulting in a reduction of 20S proteasome-mediated degradation of ubiquitin-conjugated proteins. This is predicted to lead to an increase in an accumulation of abnormal pr oteins, which ultimately contribute to neuronal degeneration and death . Based on our hypothesis and on studies published by others, we propo se that a combination of nonsteroidal anti-inflammatory drugs, which i nhibit the synthesis of PGs, and antioxidant vitamins, which quench fr ee radicals and both of which have been recently reported to be of som e value in AD treatment when used individually, may be much more effec tive in the prevention and treatment of AD than the individual agents alone.