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2007 Grant - Link
Structure/Function Analysis of In Vivo Beta-Amyloid Peptide Toxicity
Christopher D. Link, Ph.D.
University of Colorado
Candidate for 2007 Zenith Fellows Award
A key feature of Alzheimer's disease is the accumulation of a tiny protein fragment called beta-amyloid. Although much evidence indicates that beta-amyloid is an important toxic factor in the disease, scientists know relatively little about its mechanism of action.
One method that scientists use to determine a protein's mechanism of action
is to identify mutations that block the protein's function. Such mutations typically involve the substitution of one amino acid with another. Amino acids are the building blocks of cells.
Christopher D. Link, Ph.D., and colleagues have begun searching for a beta-amyloid mutation that can block the toxic activities of this protein fragment. Such a mutation could potentially reveal the molecular actions underlying amyloid toxicity. Since no antitoxic beta-amyloid mutation has been found in nature, Dr. Link's team has been engineering mutations in the laboratory. They also have developed roundworms genetically altered to produce some of these mutations. The scientists have found that one mutation, called a Glycine 37-to-Leucine substitution, dramatically reduces the toxic effects of beta-amyloid in the worms. Moreover, their work has indicated that certain oligomers, or tiny clusters of a few beta-amyloid molecules, may be the most toxic amyloid structures.
For this grant, Dr. Link's team will conduct a more expansive study with animal models to test the validity of their initial findings. Such efforts could shed new light on the structure and underlying mechanisms of the most toxic forms of beta-amyloid. Ultimately, the study's results might lead to novel Alzheimer drugs that could block amyloid toxicity.