Eduardo Castaño, M.D.
Instituto de Química y Fisicoquímica
Buenos Aires, Argentina

2003 Investigator-Initiated Research Grant

The protein fragment beta-amyloid, clipped from the parent molecule amyloid precursor protein (APP), is the prime suspect in the death of brain cells in Alzheimer's disease. Some recent scientific evidence points to the possibility that beta-amyloid accumulates in the brain because the mechanisms designed to clear the fragment are not functioning properly. One of the molecules that may be involved in clearing beta-amyloid from the brain is insulin-degrading enzyme (IDE). As with many other proteins, brain IDE levels may gradually decline with age, enabling beta-amyloid levels to rise and eventually overcome the other mechanisms designed to remove the fragment.

Eduardo Castaño and his colleagues will measure IDE levels in the brains of aging genetically engineered mice that have had the gene for APP inserted into their cells and, as a result, produce excess beta-amyloid. The team will also explore the possibility that slight variations in the length of beta-amyloid influence its clearance from the brain. In cells grown in the laboratory, the researchers will try to determine whether the longer beta-amyloid fragments, which predominate in the brains of people with Alzheimer's, are more resistant to being cleared and may even tend to inactivate IDE. Increasing beta-amyloid clearance from the brain, perhaps by therapies targeted to IDE, might offer an effective treatment strategy for Alzheimer's.