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2017 Grants - Sun
A Genomic Screen to Identify Endogenous Regulators of APP/BACE Interaction
Jichao Sun, Ph.D.
University of Wisconsin-Madison
2017 Alzheimer's Association Research Fellowship (AARF)
What genetic elements regulate the formation of Beta-amyloid?
Beta-amyloid, a protein fragment, is known to form amyloid plaques and other toxic clumps that can promote brain cell damage and cell loss in Alzheimer's disease. This fragment is "clipped" from its parent molecule, amyloid precursor protein (APP), in a multi-stage process. The first cutting action is made by a protein called beta-secretase 1 (BACE-1), and scientists are now examining how BACE-1 activity can be prevented as a possible Alzheimer's therapy. One approach is to prevent BACE-1 from physically interacting with and cutting APP. BACE-1 and APP are produced inside the nerve cell and packaged into separate spherical containers called vesicles. These vesicles must meet up within the nerve cell for BACE-1 to act on APP and produce beta-amyloid. If the BACE-1 and APP-containing vesicles could be prevented from coming together inside nerve cells, then toxic beta-amyloid would not be produced. However, scientists remain uncertain exactly how this meeting of BACE-1 and APP occurs.
In a novel experiment with fluorescent tracers, Jichao Sun, Ph.D., and colleagues successfully visualized the convergence of APP and BACE-1 in brain cells grown in a dish. They will use their current grant to study the biological mechanisms that underlie the process they observed. APP/BACE-1 convergence requires a wide range of genetic factors in order to take place. To identify these factors, the researchers will conduct a genetic screening test to find genes and cellular pathways that determine how and when APP and BACE-1 converge.
The results of Dr. Sun's efforts will shed new light on the genetic factors involved in Alzheimer's disease by studying APP-BACE-1 interaction. With this information, they could also identify novel, precisely-targeted dementia therapies.