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2006 Grant - Bredesen
A Role for the Intracytoplasmic Cleavage of APP in Alzheimer's Disease
Dale E. Bredesen, M.D.
Buck Institute for Age Research
2006 Investigator-Initiated Research Grant
The beta-amyloid protein fragment is clipped from a larger molecule called amyloid precursor protein (APP). Because beta-amyloid is believed to be a key toxic factor in Alzheimer's disease pathology, the discovery of other molecules that interact with it are of particular interest.
Dale Bredesen, M.D., and colleagues have reported on another protein fragment called APP-C31, which is also clipped from APP. They observed in cell studies, that APP-31 was generated when APP molecules bind together with tiny clusters of beta-amyloid inside cells. In studies with genetically altered mice that develop an Alzheimer-like disorder, the researchers found that inhibiting the production of APP-C31 prevented the development of several features of Alzheimer's disease in the mice.
Dr. Bredesen has hypothesized that (1) APP-C31 mediates the toxicity of beta-amyloid, (2) APP molecules not yet missing the APP-C31 fragment may have some protective effect on cells or (3) a combination of these two factors inhibit Alzheimer pathology. To test this hypothesis, the investigators will generate new lines of Alzheimer-like mice that enable them to look at the factors independently. Findings from this work may improve our under-standing of Alzheimer's disease processes and suggest new avenues of investigation for disease-modifying treatments.