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2006 Grant - Abraham
The Significance of APP Dimerization in Alzheimer's Disease
Carmela R. Abraham, Ph.D.
2006 Investigator-Initiated Research Grant
Accumulation of a small protein fragment called beta-amyloid is a hallmark of Alzheimer's disease. Beta-amyloid is culled from a larger protein called the amyloid precursor protein (APP). With the exception of a small percentage of people with inherited forms of the disease, scientists are not sure what drives the accumulation of beta-amyloid. In fact, little is known about the function and properties of APP itself. This gap in knowledge is a major impediment to understanding the production of beta-amyloid.
Carmela Abraham, Ph.D., and colleagues plan to study the properties and physiological function of APP. One of their major aims is to determine what form APP assumes in neurons. There are indications, for example, that the proteins form pairs, or dimers, either with themselves or with other proteins. The research team plans to study these protein-protein interactions.
Abraham has devised a technique that will enable her to visualize when APP has formed a dimer. The technique relies on a yellow fluorescent protein, or YFP. If YFP is cut in half, it loses its fluorescence, but if the two halves are brought back together, fluorescence is restored. By attaching one half of YFP to APP and the other to a different molecule of APP or an entirely different protein, Abraham will be able to determine if APP dimerizes with itself or other proteins-yellow fluorescence will indicate formation of a dimer.
There are indications that beta-amyloid production depends on dimerization of APP. Abraham will use the fluorescence technique to search for small molecules that inhibit APP dimerization and then test those same molecules to see if they prevent formation of beta-amyloid. The findings could lead to new developments in disease-modifying treatments.