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2015 Grants - Feng
Development of New Therapeutic Reagents for Alzheimer’s Disease
Liang Feng, Ph.D.
2015 New Investigator Research Grant
Can novel drugs be developed that inhibit the production of toxic beta-amyloid without having unacceptable side effects?
A focus of research into understanding and potentially treating Alzheimer’s disease is beta-amyloid, a protein fragment that may be toxic to nerve cells and can accumulate into clumps called plaques, a hallmark of Alzheimer’s disease. Beta-amyloid is produced from its parent protein by the cutting action of a series of proteins that function as molecular scissors. The protein responsible for the final step of producing beta-amyloid is known as gamma-secretase.
Scientists have developed numerous compounds that inhibit gamma-secretase. However, because gamma-secretase has other important functions, these potential drug candidates have had unacceptable side effects. Recently, however, a few compounds have been discovered that inhibit the ability of gamma-secretase to produce beta-amyloid, but not interfere with its other normal functions. Unfortunately, these drug candidates have not yet been potent enough or specific enough to be used as effective treatments.
Liang Feng, Ph.D., and colleagues have proposed a series of studies to develop novel molecules and test them to determine those that may modulate the activity of gamma-secretase. Specifically, the team will determine if they can modulate gamma-secretase in a way that reduces its production of toxic beta-amyloid without interfering with its other normal functions. They will perform a series of studies in cells growing in laboratory dishes to test molecules that can alter and “lock” gamma-secretase into a shape that cannot produce beta-amyloid but still allows other essential functions.
These studies represent the first steps in understanding how to modulate the activity of gamma-secretase to prevent or slow the production of toxic beta-amyloid in the brain. The results of these studies could lead to the development of novel therapies to prevent, halt or slow Alzheimer’s disease.