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2010 Grants - Town
Macrophage TGF-beta–smad 2/3 Inhibitor Therapy in Transgenic Alzheimer Rats
Terrence C. Town, Ph.D.
Cedars-Sinai Medical Center
Los Angeles, California
2010 Zenith Fellows Award
TGF-beta (transforming growth factor-beta) is a receptor on the surface of cells that mediates many important functions throughout the body. When TGF-beta is activated, it activates other proteins inside the cell, which cause changes in the way the cell functions. One class of such proteins is known as smads, particularly smad-2 and smad-3 (smad 2/3).
Terrence C. Town, Ph.D. and colleagues recently used molecular techniques to inhibit signaling from TGF-beta to the smad-2/3 proteins in mice expressing Alzheimer-like pathology. The researchers showed that inhibition of this pathway inhibited the development of Alzheimer pathology in these animals. They also showed that this effect was mediated by cells in the blood known as macrophages. After inhibition of the TGF-beta–smad-2/3 pathway in macrophages, these cells were able to enter the brain and remove amyloid, one of the main pathologic features of Alzheimer's disease.
Because it is impractical to make genetic changes in living organisms, Dr. Town's team developed a drug candidate that inhibits the TGF-beta–smad-2/3 pathway. They have proposed a series of studies to optimize the efficacy of this drug candidate and test its efficacy in animal models.
The researchers will begin by testing different ways to direct their drug candidate so that it selectively affects macrophages. They will then use imaging techniques in living animals to determine the doses needed to cause macrophages to enter the brain. Finally, Dr. Town and colleagues will test the efficacy of their drug candidate in rats that have been genetically modified to express Alzheimer-like pathology. These studies represent significant steps in the development of a potential drug for prevention or treatment of Alzheimer's disease.