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2006 Grant - Arispe
Blocking the Beta-Amyloid Ion Channels Protect the Cell
Nelson Arispe, Ph.D.
The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.
2006 Zenith Fellows Award
A neuron has tiny pores, or channels, in its membrane that regulate the flow of ions, or electrically charged chemical particles, into and out of the cell. This activity is a function of the nervous system's communication network.
A key feature of Alzheimer's disease is the accumulation of a tiny protein fragment called beta-amyloid. Although there is much evidence that beta-amyloid is an important toxic factor in the disease, its mechanism of action is not well understood. One hypothesis suggests that beta-amyloid creates abnormal ion channels in the membrane of neurons. This "unregulated leaking" of ions could, if extensive enough, activate processes that provoke the death of cells. However, scientists have observed that not all cells are equally affected by beta-amyloid, and some cells have shown to be resistant to amyloid toxicity.
Nelson Arispe, Ph.D., and colleagues hope to prove that active beta-amyloid ion channels initiate the processes responsible for the toxic action of beta-amyloid on susceptible neurons. In preliminary studies, they created synthetic protein fragments that blocked beta-amyloid ion channels in certain laboratory cells. Early results indicated that these channel blockers also prevented amyloid toxicity in neurons of living animal brains.
Dr. Arispe's team proposes to develop a greater variety of synthetic channel blockers and to test their effectiveness in various neurons. They also will further investigate the possible correlation between ion channel formation and beta-amyloid toxicity in many types of brain cells. This work should enable them to evaluate the biochemical processes responsible for the death of cells susceptible to amyloid toxicity-and the survival of cells resistant to such toxicity. Results from the investigation could lead to a new therapeutic approach to Alzheimer's disease.