New insight into Alzheimer's disease.
A research group now suggests that beta-amyloid binds to a protein--the alpha 7 nicotinic acetylcholine receptor--on the surface of nerve cells and thus triggers a chemical modification of tau that might lead to tangle formation. Binding of beta-amyloid to this receptor ultimately kills nerve cells, perhaps via a previously unsuspected buildup of beta-amyloid inside the cell, the scientists suggest.
This novel view of Alzheimer's disease was offered in three presentations by investigators at the R.W. Johnson Pharmaceutical Research Institute in Spring House, Pa. In the first, Hoau-Yan Wang noted that many scientists believe that beta-amyloid directly kills certain nerve cells, so-called cholinergic neurons, but they can't yet explain how. Wang presented evidence that cholinergic neurons sport copies of the alpha 7 receptor and that beta-amyloid binds tightly to them.
"This may contribute to the dysfunction and degeneration of the neurons," he says. A compound that prevents beta-amyloid from binding to the receptor thwarts the ability of the amyloid protein to kill nerve cells, reports Wang.
Next, Daniel Lee offered data indicating that the binding of beta-amyloid to this receptor induces phosphate groups to attach to tau. Increased tau phosphorylation is a hallmark of Alzheimer's disease and may create tangles by altering tau's stability. "This is the first connection of beta-amyloid to tau phosphorylation by a known receptor," says Lee.
Finally, Michael R. D'Andrea offered the controversial idea that plaques observed in patients' brains arise from clumps of beta-amyloid in living cells. He says that the alpha 7 receptor may draw beta-amyloid into a cell until the cell dies and disintegrates, leaving an extracellular plaque. The distribution, density, and shape of plaques support this idea, he argues.
An Alzheimer's drug already in tests on patients targets the same nerve cell receptor that D'Andrea's group has highlighted, report Edwin M. Meyer of the University of Florida in Gainesville and his colleagues. The drug protects cells from amyloid toxicity, but Meyer remains skeptical that alpha 7 receptors represent a direct target of beta-amyloid.
"I love the idea because it makes the receptor more relevant to Alzheimer's disease, but it's not fitting into the data. There's an awful lot of cells affected by [beta-amyloid] that don't have alpha 7 receptors," he says.
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|Article Type:||Brief Article|
|Date:||Nov 13, 1999|
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