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2007 Grant - Pratico
The Functional Role of Lipoxygenase in Normal Aging and Alzheimer's Disease
Domenico Pratico, M.D.
Associate Professor of Pharmacology
University of Pennsylvania
2007 Zenith Award Candidate
Aging is the greatest risk factor for Alzheimer's disease, which is estimated to affect 1 in 8 Americans over age 65 and more than 40 percent of those over 85. This sharply rising prevalence with age suggests that accumulating biological wear and tear over time may increase the vulnerability of nerve cells to Alzheimer's disease and related disorders. Two common mechanisms that may help create this vulnerability are inflammation and chemical reactions between oxygen and other essential cellular molecules. An enzyme called lipoxygenase is involved in biological processes implicated in both inflammation and oxygen-related damage.
Domenico Pratico, M.D., and his team have shown that lipoxygenase occurs abundantly throughout the brain, and that levels rise with age. They have also determined that individuals with Alzheimer's disease and mild cognitive impairment (MCI) tend to have higher levels than those with no impairment. In work with mice genetically engineered to produce human beta-amyloid, they have shown that shutting down the gene coding the lipoxygenase "blueprint" reduces the amount of beta-amyloid the animals produce as they grow older.
In this project, Practico and colleagues propose further work in custom-designed laboratory cell cultures to determine the exact mechanisms by which lipoxygenase appears to influence beta-amyloid production in the Alzheimer-like mice. They will focus on how chemical pathways involving lipoxygenase may interact with steps in processing of amyloid precursor protein (APP) by the enzymes alpha-, beta-, and gamma-secretase. APP is beta-amyloid's parent molecule.
Confirming and elucidating these interactions could establish lipoxygenase as a potential new therapeutic target in Alzheimer's disease. Drugs that block the activity of lipoxygenase are a recent important addition to asthma treatment options. If the enzyme could be validated as a viable Alzheimer target, drug development could build on and benefit from the known track record of lipoxygenase-blocking asthma treatments.