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2005 Grant - Sanders

Familial Alzheimer's Disease Mutations in the Amyloid Precursor Protein

Charles R. Sanders, Ph.D.
Vanderbilt University Medical Center
Nashville, Tennessee

2005 New Investigator Research Grant

Beta-amyloid is a tiny protein fragment that tends to clump together in the Alzheimer's disease brain. It is clipped in a two-stage process from a larger molecule called amyloid precursor protein (APP). The second cut determines the length of the beta-amyloid fragment. A shorter version of beta-amyloid is less likely to clump together than a longer version. In Alzheimer's disease, the second cut seems to result predominantly in the longer problematic version.

The protein that provides the "genetic blueprint" for APP is also called APP. Some forms of the rare, inherited form of Alzheimer's disease are caused by a mutation in the APP gene. Although a number of different mutations are possible, they all seem to result in slight variations in the APP protein near the sight of the second cut.

Charles R. Sanders, Ph.D., and colleagues are studying this particular region of the APP protein. They will use a technology that enables them to create a molecular-level "snapshot of the protein." They will compare the snapshots of a normal APP protein with versions of the protein resulting from various Alzheimer-associated APP gene mutations. These comparison studies may reveal what goes wrong with the disease-related form of the protein that result in a long beta-amyloid fragment. This information may provide insight that can lead to the design of disease-modifying therapies to suppress the incorrect clipping of APP.