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2010 Grants - Abraham
Modulators of APP Dimerization as Novel Therapeutics for Alzheimer's Disease
Carmela R. Abraham, Ph.D.
Boston University Medical Campus
2010 Investigator-Initiated Research Grant
One of the key features of Alzheimer's disease is the production and accumulation of the protein fragment beta-amyloid. Beta-amyloid, in various forms, is toxic to nerve cells and it can aggregate into amyloid plaques, one of the hallmarks of Alzheimer pathology. Beta-amyloid is produced when its parent molecule, amyloid precursor protein (APP), is cut into fragments. Certain genetic mutations in APP are known to increase a person's risk of Alzheimer's disease. Evidence also suggests that levels of certain forms of beta-amyloid are increased if APP molecules bind together in pairs (dimerization).
Carmela R. Abraham, Ph.D., and colleagues are studying how dimerization of APP affects the production of beta-amyloid, and whether the dimerization process could be a useful target for drugs to halt or slow the progression of Alzheimer's disease. The researchers will measure how normal and mutant APP molecules dimerize using an optical method that detects changes in fluorescence when dimerization occurs. Their preliminary studies suggest that normal and mutant APP dimerize differently. In a related study, Dr. Abraham and colleagues will study a large number of drug candidates to determine which drugs inhibit the dimerization of APP, and whether those drugs also reduce the subsequent production of beta-amyloid. If successful drug candidates are identified, Dr. Abraham's team will extend their studies to determine if the drugs reduce the development of Alzheimer-like pathology in mouse models of the disease. These studies could lead to the identification of an important new drug target for slowing or halting the development of Alzheimer pathology.