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Protein Glitch May Be Early Problem In Inherited Alzheimer's

Johns Hopkins scientists have assembled the first clues to the behavior of presenilin, a protein linked to an inherited form of Alzheimer's disease.

In a report published in the July issue of Neuron, they show that presenilin normally cleaves in two and that a disease-causing mutation in presenilin can prevent the cleavage.

Cleavage is an important change for a protein--it probably has a significant effect on what the protein does. If researchers can find where presenilin cleaves and the enzyme that cleaves it, intervening at this point with drugs or other treatments might be ideal, according to Sangram Sisodia, Ph.D., an associate professor of pathology and neuroscience.

Sisodia and Gopal Thinakaran, Ph.D., David Borchelt, Ph.D., and Michael Lee studied presenilin in cell cultures and in mice that contained copies of the human presenilin gene.

Presenilin is a long protein that snakes in and out of the membranes of nerve cells. It is found in an altered form in nearly 60 percent of all "early onset" familial Alzheimer's disease (FAD) cases, cases where symptoms first appear in patients in their late 20s to the their late 50s.

Because presenilin is present only at very low levels, Sisodia notes, it's unlikely to be directly causing the widespread damage to nerve cells seen in FAD, but it may interfere with other proteins that could. Like dominoes falling, a change in presenilin sets off a chain reaction.

"Think of it as a cascade," says Sisodia. "We don't know how many steps there are in this cascade, but we have a theory about where the cascade is headed."

According to Sisodia, mutated forms of presenilin may influence the formation of plaques in the brain that are among the earliest signs of Alzheimer's disease.

Hopkins researchers currently are looking at mice in which the gene for presenilin is knocked out so that presenilin's function may be revealed by its absence.

Scientists estimate that 15 percent of Alzheimer'
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Contact: Michael Purdy
mpurdy@welchlink.welch.jhu.edu
410-955-8725
Johns Hopkins Medical Institutions
7-Aug-1996


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