Alzheimer's disease (AD) is a tragically common and devastating illness for which there is no effective therapy. Although the causative event(s) responsible for the disease are not known, it is more and more evident that inflammation and oxidative stress are features of AD brains. Aging is one of the strongest risk factors for developing AD, and oxygen-mediated events are being considered as possible mechanisms responsible for the increasing neuronal vulnerability in aging. Lipoxygenases (LO) are enzymes that can insert oxygen into a molecule of arachidonic acid and thereby synthesize inflammatory eicosanoids or form lipid peroxidation products. One of the most abundant LO in the central nervous system (CNS) is neuronal 12/15LO, whose activity and protein levels are increased in AD compared to control brains. However, despite some circumstantial evidence suggesting that this enzyme might play a role in neurodegeneration, a biological role for 12/15LO in the CNS has yet to be established. The long-term objective of this proposal is to understand the importance of 12/15LO in the CNS with particular emphasis on AD. The availability of a well-characterized mouse model of AD-amyloidosis (Tg2576) together with a specific inhibitor of the 12/15LO enzyme activity, and mice genetically deficient for 12/15LO gene expression should allow us to elucidate this clinically relevant issue.
In Specific Aim 1 we will investigate whether pharmacological inhibition of 12/15LO activity has any effect on the phenotype of Tg2576, then we will seek confirmation of these results by cross-breeding mice deficient for 12/15LO with Tg2576.
In Specific Aim 2 we will characterize cellular and molecular factors that regulate the expression of 12/15LO in primary neurons, and will investigate the relationship between this enzymatic pathway and the amyloid hypothesis of AD. In summary, these studies will elucidate the neurobiology of the 12/15LO metabolic pathway and its putative role in AD pathogenesis. Such data are clinically relevant and should provide important clues to the potential use of specific 12/15LO inhibitors as novel therapeutic agents for preventing or limiting the evolution and/or progression of AD.
