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2016 Grants - Roy
Identifying Molecules that Attenuate APP and BACE-1 Interactions
Subhojit Roy, Ph.D.
University of California, San Diego
La Jolla, CA
2016 Collaboration 4 Cure (C4C) Grant
Can interfering with the interaction between APP and BACE-1 in nerve cells reduce beta-amyloid protein production?
The production of beta-amyloid protein in the brain can lead to the formation of amyloid plaques, a hallmark of Alzheimer’s disease. Beta-amyloid is produced from its parent protein, amyloid precursor protein (APP), but the cutting action of an enzyme called beta-secretase 1 (BACE-1). Although inhibiting BACE-1 activity is one way to reduce beta-amyloid production, the BACE-1 inhibitors investigated thus far have caused unwanted side effects because they cut other important proteins. An alternative approach to reducing beta-amyloid production is to prevent BACE-1 from physically interacting specifically with 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 beta-amyloid would not be produced.
Dr. Subhojit Roy has developed a method that can track BACE-1 and APP-containing vesicles as they move inside nerve cells growing in a laboratory dish. This method uses fluorescent signals that light up only when BACE-1 and APP-containing vesicles come together inside nerve cells. The researchers will use this system to test whether specific drug-like molecules are effective at preventing the BACE-1 and APP-containing vesicles from meeting. The researchers will rapidly screen thousands of individual drug-like molecules to determine which ones inhibit the BACE1-APP interaction — an approach called high-throughput screening. Any molecules that are found to prevent the BACE-1 and APP-containing vesicles from interacting will be selected for further testing in animal studies.
These new methods may provide a way to quickly identify molecules that can prevent BACE-1 and APP-containing vesicles from coming together inside nerve cells—thus preventing beta-amyloid production. The novel drug candidates identified can then be further investigated as potential treatments to slow, halt or prevent Alzheimer’s disease.