Researchers are a step closer to understanding how Alzheimer's disease takes shape—literally.
A hallmark of Alzheimer's is the presence of protein aggregates in the brain known as plaques. They are made up of various lengths and conformations of the beta amyloid protein. The proteins link end to end, forming long, threadlike structures called fibrils. Now Roland Riek and his colleagues at the Salk Institute for Biological Studies in San Diego, working with scientists at the University of Lausanne in Switzerland and the F. Hoffmann–La Roche company, have constructed a three-dimensional model of the fibrils based on their own experiments and earlier data published by others.
Riek says the model will help investigators to understand protein structure, which could lead to better targeted drugs. For example, molecules could be engineered to act as protein binding partners, thus interfering with fibril formation. Such a sticky molecule could also be used to diagnose the disease early. The model work might lend insight to other neurological disorders that involve fibril formation, such as Parkinson's disease.
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David B. Teplow, a neurology professor at the University of California, Los Angeles, not involved in Riek's work, states that the model, as it stands, may not fully represent fibrils as they exist in a patient's brain. But Teplow praises the effort, noting that it could form the basis for further structural modeling studies of other beta amyloid peptides. Riek says his group will extend the three-dimensional work to other variations of the amyloid protein, because it undergoes many conformational changes on its way to forming a fibril. “We need to try to trap them in these intermediate states,” he explains.