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.

National Institute of Health (NIH)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Petanceska, Suzana
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Temple University
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Joshi, Yash B; Giannopoulos, Phillip F; Chu, Jin et al. (2014) Modulation of lipopolysaccharide-induced memory insult, ?-secretase, and neuroinflammation in triple transgenic mice by 5-lipoxygenase. Neurobiol Aging 35:1024-31
Giannopoulos, Phillip F; Joshi, Yash B; Praticò, Domenico (2014) Novel lipid signaling pathways in Alzheimer's disease pathogenesis. Biochem Pharmacol 88:560-4
Di Meco, Antonio; Lauretti, Elisabetta; Vagnozzi, Alana N et al. (2014) Zileuton restores memory impairments and reverses amyloid and tau pathology in aged Alzheimer's disease mice. Neurobiol Aging 35:2458-64
Giannopoulos, P F; Chu, J; Joshi, Y B et al. (2014) Gene knockout of 5-lipoxygenase rescues synaptic dysfunction and improves memory in the triple-transgenic model of Alzheimer's disease. Mol Psychiatry 19:511-8
Joshi, Yash B; Di Meco, Antonio; Pratico, Domenico (2014) Modulation of amyloid-* production by leukotriene B4 via the ýý-secretase pathway. J Alzheimers Dis 38:503-6
Giannopoulos, Phillip F; Joshi, Yash B; Chu, Jin et al. (2013) The 12-15-lipoxygenase is a modulator of Alzheimer's-related tau pathology in vivo. Aging Cell 12:1082-90
Chu, Jin; Li, Jian-Guo; Ceballos-Diaz, Carolina et al. (2013) The influence of 5-lipoxygenase on Alzheimer's disease-related tau pathology: in vivo and in vitro evidence. Biol Psychiatry 74:321-8
Chu, Jin; Li, Jin-Guo; Pratico, Domenico (2013) Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles. PLoS One 8:e70991
Chu, Jin; Pratico, Domenico (2013) 5-Lipoxygenase pharmacological blockade decreases tau phosphorylation in vivo: involvement of the cyclin-dependent kinase-5. Neurobiol Aging 34:1549-54
Joshi, Yash B; Chu, Jin; Pratico, Domenico (2013) Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice. Aging Cell 12:706-11

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