Nature
August 17, 2006
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Brain Protein Discovery May Open New Avenues for Alzheimer’s Treatment
WAVE-1 protein critical for regulating connections between brain cells.

Scientists at the Fisher Center for Alzheimer’s Research at The Rockefeller University in New York City discovered that a protein called WAVE-1, found in the brain, is a key regulator of connections between brain cells. Such connections carry nerve impulses from one brain cell to another, and are necessary for brain activities that include thought, memory and other mental skills. The researchers, led by Dr. Paul Greengard — the Center’s Director and year 2000 recipient of the Nobel Prize in Physiology or Medicine — and Dr. Young Kim point out that their discovery could hold special significance for combating Alzheimer’s disease –the leading cause of dementia in the elderly. That is because one of the key features of Alzheimer’s that results in the devastating loss of memory and other mental skills is caused primarily by the loss or malfunction of connections between brain cells. So by being able to control the growth of new connections or stop the loss of old ones, doctors may one day be able to prevent or reverse dementia.

WAVE-1, which stands for “Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1,” affects the “cytoskeleton” inside brain cells. “Cytoskeleton” means, “cell skeleton.” It is the intricate, minute filigree of proteins inside a living cell that allows the cell to take on specific shapes. In nerve cells, the cytoskeleton functions to produce both the long branches of the nerve cell, as well as the thousands of tiny bumps, called “spines” that dot the branches and form connections with other nerve cells. Fisher scientists found that when molecules containing phosphorous are added to WAVE-1 (a natural process called “phosphorylation”), the cytoskeleton is prevented from forming spines. In contrast, when phosphorous-containing molecules are removed (a natural process called “dephosphorylation”), WAVE-1 stimulates the cytoskeleton to produce a lush crop of spines.

By working out the molecular mechanism of spine formation and depletion, as Fisher scientists have done, it will be possible to identify potential drug targets. These are protein molecules that form the mechanism by which WAVE-1 controls the cytoskeleton. By finding and creating drugs that modify the functions of these proteins, scientists hope to modify the course and severity of Alzheimer’s disease.