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2005 Grant - Vetrivel
Exploring Gamma-Secretase Function in Lipid Raft Membrane Microdomains
Kulandaivelu Vetrivel, Ph.D.
University of Chicago
2005 New Investigator Research Grant
Accumulation in the brain of a small protein fragment called beta-amyloid is one of the hallmarks of Alzheimer's disease. This fragment, which is toxic to nerve cells, is clipped from the larger amyloid precursor protein (APP) by the action of two enzymes called beta-secretase and gamma-secretase. Inhibiting either of these secretases could provide a means to limit production of beta-amyloid and slow or prevent progression of Alzheimer's. For this reason, it is important that researchers learn as much about these two enzymes as possible.
Kulandaivelu Vetrivel, Ph.D., and colleagues will study the function of gamma-secretase in "lipid rafts." These rafts are microscopic globs composed of cholesterol, other fats and proteins. Recent evidence suggests that these rafts harbor gamma-secretase and APP and that the rafts could be major sites for production of beta-amyloid.
The researchers will examine how gamma-secretase gets on and off these rafts. The enzyme comprises at least four separate components, and Vetrivel and colleagues recently discovered that their presence on the rafts is sensitive to cholesterol. This relationship will be further explored. In addition, because inhibiting the enzyme could compromise other important processes that would lead to potentially toxic side-effects, it is important to know how the location of the enzyme relates to its biological activities. For this reason the investi-gators will examine if gamma-secretase processes any other proteins on these lipid rafts. The outcome of this work may answer questions about key disease processes and suggest new therapeutic strategies.