The Neurobiology of 5-Lipoxygenase

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a chronic and complex neurodegenerative disease that causes progressive loss of cognitive functions with dementia and for which there is no cure. Aging is a strong risk factor for developing AD, and dysregulated oxygen-mediated events as well as inflammatory processes are considered potential biological links between aging and the disease pathogenesis. 5-Lipoxygenases (5LO) is an enzyme that oxidizes fatty acids and thereby synthesizes inflammatory lipid mediators (leukotrienes), and lipid peroxidation products (hydroxyperoxides), both of which are also potent oxidants. This enzyme is widely expressed in the central nervous system (CNS). However, despite some circumstantial evidence suggesting that it may play a role in neurodegeneration, a definitive biological role for 5LO in the CNS has yet to be established. We recently showed that the expression levels of 5LO are increased in the CNS with aging particularly in the hippocampus, and that compared to controls this enzyme is upregulated in AD brains. We also demonstrated that genetic ablation of 5LO results in reduced endogenous A¿ levels in wild type mice, and significantly less A¿ deposits in the Tg2576 mice, a mouse model of AD-like amyloidosis. Further, in cell culture systems 5LO activation and pharmacologic inhibition results in increased and reduced A¿ formation, respectively. Together, these data provide strong support for the hypothesis that this enzymatic pathway could play a functional role in AD pathogenesis, and represent a novel therapeutic target for the disease. The main goal of the current proposal is to test the hypothesis that 5LO activation results in the formation of bioactive lipids, which in turn modulate metabolic pathways germane to the AD neuropathology. The elucidation of the molecular and cellular mechanisms whereby this enzyme system influences the production and turnover of A¿ and the metabolic fate of its precursor protein, APP, is extremely important since it could establish a novel pathway relevant to the development of AD pathology, and become a new therapeutic target. Thus, if successful, our findings will provide important clues for future studies with specific 5LO inhibitors as novel therapeutic agents for preventing or limiting the evolution and /or progression of AD. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a disease that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its cause(s) remain unknown, and there is no cure for it. 5Lipoxygenase (5LO) is a protein whose levels and activity are increased in AD compared with healthy control brain, and could be directly involved in the development of the disease. If we prove this hypothesis, our findings will provide important information for future human studies with specific drug inhibitors of 5LO as a novel therapy for the treatment of this devastating disease.