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Dueling proteins fuel Alzheimer's debate.

A key mystery of Alzheimer's disease revolves around the unusual protein deposits found in patients' brains during autopsy. For years, scientists have debated whether these protein "plaques" actually cause the neurological disorder or are simply a by-product of the disease-fostered deaths of nerve cells.

Now researchers who have injected the protein, known as beta amyloid, into the brains of rats report that it triggers cell death resembling that seen in Alzheimer's victims. This finding establishes for the first time a direct link between beta amyloid and neuron destruction in live animals, says study coauthor Neil W. Kowall of Massachusetts General Hospital in Boston.

Moreover, the investigators discovered that another brain protein, called substance P, prevents the induced brain damage in rats. This raises the tantalizing, though still remote, prospect of an effective treatment for a disease that robs many elderly of their memories and minds.

The new report "is another piece of the puzzle," Kowall says. "But there are many other pieces to be found and put together."

Earlier findings indicated that beta amyloid is toxic to lab-cultured nerve cells (SN: 7/29/89, p.68). In the new study of 69 rats, the protein showed similar toxicity when injected into the hippocampus of the brain, Kowall and his colleagues report in the Aug. 15 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES.

One week after the injections, the researchers killed the rats and analyzed samples of brain tissue. In addition to toxicity, they noted that brains injected with beta amyloid showed antibodies similar to those detected in Alzheimer's patients. Despite these similarities, the injections do not duplicate Alzheimer's in rats, says Kowall. For example, clots or "tangles" of insoluble proteins within neurons -- another feature characteristic of Alzheimer-afflicted brains -- did not appear in the rat tissues studied.

Substance P -- injected directly into the brain with the beta amyloid or a day or so later -- reduced the extent of toxicity, preventing amyloid-induced neuron death and the arrival of Alzheimer's-like antibodies. Kowall says. Abdominal injections of substance P elicited similar results, suggesting that it can cross the blood-brain barrier, he adds.

Kowall also notes that substance P's actions were dose-dependent: The more injected, the stronger the protection. Previous research indicated that this protein, a neurotransmitter naturally present in the brain, is depleted in Alzheimer's patients, says Bruce A. Yankner of Harvard Medical School in Boston, who directed the rat study.

Substance P's effect "is going to be an important clue or avenue for drug development," says Zaven Khachaturian of the National Institute on Aging, which helped fund the new study.

Scientists still need to replicate the new results and extend them to higher animals. And most researchers remain cautious about the protein's potential as a treatment. "Whether substance P is practical to use is very open still," Kowall says. "It's very premature to be thinking about therapy," agrees Donald L. Price, a neuropathologist at Johns Hopkins University School of Medicine in Baltimore.

In a related development had underscores the importance of amyloids, investigators report in the July 18 NATURE that mice genetically engineered to over-produce an amyloid precursor protein (of which beta amyloid is a fragment) develop plaques similar to those seen in Alzheimer's. If these mice show memory loss and other signs of the disease, researchers will have a new model in which to pursue their studies of Alzheimer's, asserts study director Barbara Cordell of California Biotechnology, Inc., in Mountain View.

Price calls Cordell's paper "important" and suggests that researchers could settle the beta amyloid debate by creating mice with the amyloid gene mutation recently found in some cases of inherited Alzheimer's (SN: 2/23/91, p.117).

"If those animals develop behavioral difficulties and plaques and tangles," says Price, "then you can say [beta amyloid] causes Alzheimer's."
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Title Annotation:beta amyloid deposits in patients' brains linked to Alzheimer's disease
Author:Travis, John
Publication:Science News
Date:Aug 24, 1991
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