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2005 Grant - Murphy
The Two Faces of Transthyretin: TTR's Role in Beta-Amyloid Aggregation
Regina M. Murphy, Ph.D.
University of Wisconsin
2005 Investigator-Initiated Research Grant
A prime suspect in the pathology of Alzheimer's disease is a tiny protein fragment, called beta-amyloid, which tends to aggregate, or clump together. In an effort to model disease processes, researchers have developed genetically altered mice that overproduce human beta-amyloid. While beta-amyloid aggregates in these mice and the mice develop neuron dysfunction and memory impairments, they do not exhibit a significant loss of brain cells as occurs in Alzheimer's. The reason for this phenomenon has been unclear.
Recent studies have shown the Alzheimer-like mice may respond to the overproduction of beta-amyloid by producing large amounts of another protein called transthyretin (TTR). TTR appears to bind to beta-amyloid and prevent aggregation, thereby enabling other processes to degrade beta-amyloid.
Oddly enough TTR, like beta-amyloid, can form aggregates associated with the pathology of other diseases. Thus, the TTR protein may have "two faces" —one of being capable of aggregating itself and the other of preventing the aggregation of beta-amyloid.
Regina M. Murphy, Ph.D., and associates aim to characterize the biochemical relationship between beta-amyloid and TTR and identify compounds that safely mimic the binding of TTR to beta-amyloid and its anti-aggregation properties. This work may reveal a valid approach for disease-modifying Alzheimer treatments.