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2008 Grants - Yasuda
Amyloid-Beta-Induced Rho GTPase Signaling in Dendritic Spines
Ryohei Yasuda, Ph.D.
Duke University Medical Center
Durham, North Carolina
2008 New Investigator Research Grant
One of the changes observed in the brains of persons with Alzheimer's disease is degeneration of synapses, the specialized regions of nerve cells that enable them to send rapid signals to other nerve cells. Synapses often exist on "spines," small protuberances on the surface of dendrites (the "branches" of a neuron that receive transmitted signals). Several studies have found that people with Alzheimer's have fewer dendritic spines than healthy individuals.
In order to maintain dendritic spines, nerve cells must maintain an internal "skeleton." There is evidence that this skeleton becomes abnormal when nerve cells are exposed to beta-amyloid, possibly explaining the loss of dendritic spines in Alzheimer's disease. Beta-amyloid (also known as amyloid-beta) is a protein fragment strongly implicated in Alzheimer neurodegeneration. Although the mechanisms that mediate the effects of beta-amyloid on the cell's internal skeleton are not known, key proteins responsible for maintaining the internal skeleton have been identified. These proteins are actin, which forms the skeleton itself, and Rho GTPase, a signaling protein that is crucial for regulating the structure of the actin skeleton.
Ryohei Yasuda, Ph.D., and colleagues are studying how the internal skeleton of nerve cells is affected by exposure of the cells to beta-amyloid. They have developed a high-resolution microscopy technique that enables them to visualize and record the activity and binding of Rho GTPase in single dendritic spines. Using this technique, they have been able to show that activation of the synapse during normal activity can cause activation of Rho GTPase and enlargement of the dendritic spine.
The researchers plan to use their new techniques to examine how beta-amyloid affects the activation of Rho GTPase and how those effects lead to changes in the structure of the dendritic spine. These experiments will probe the mechanisms behind one of the central causes of cognitive decline in Alzheimer's disease and may improve our understanding of the role of beta-amyloid in causing cognitive impairment.