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2008 Grants - Jung
Novel Activator Genes of Gamma-Secretase (SecAs) for APP-Favorable Cleavage
Yong-Keun Jung, Ph.D.
Seoul National University
Seoul, South Korea
2008 Investigator-Initiated Research Grant
The protein fragment beta-amyloid may damage cell-to-cell communication and induce brain cell loss in Alzheimer's disease. Beta-amyloid is clipped from its parent molecule, amyloid precursor protein (APP), in a two-stage process. The second cut is made by gamma-secretase, a complex of several proteins. One strategy to inhibit the production of beta-amyloid involves blocking gamma-secretase activity. A potential problem with this strategy is that gamma-secretase has other functions in the cell, including the processing of a protein called Notch. Therefore, researchers hope to identify genes that activate gamma-secretase in a way that directs it to target APP instead of other proteins.
In preliminary studies, Yong-Keun Jung, Ph.D., and colleagues used sophisticated genetic screening techniques to identify several gamma-secretase-activating genes called secAs. Two of the proteins encoded by these genes, called secA1 and secA2, may stimulate gamma-secretase to produce beta-amyloid but not to process Notch or other proteins.
Dr. Jung's group plans to characterize more clearly the role of secAs in the activation of gamma-secretase. Using cultured cells, the researchers will further test whether various secAs dispose gamma-secretase to target APP, Notch or other proteins. Next, the team will study data from the brains of people with Alzheimer's disease. Such brains will likely have lower than normal levels of various secAs. Finally, Dr. Jung and colleagues will analyze the effects of increased secA levels in the brains of mice genetically engineered to develop Alzheimer-like symptoms. These effects may include reduced beta-amyloid accumulations and less acute memory loss.
Results of Dr. Jung's research could identify secAs as novel genetic targets in the fight against Alzheimer's disease.