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Progress Toward Therapy for Alzheimer’s Reported : Medicine: Tests on rats show injection of a brain hormone can block cell degeneration seen in the disease.

TIMES SCIENCE WRITER

Boston researchers have demonstrated in rats that injections of a naturally occurring brain hormone can block a type of cell degeneration seen in Alzheimer’s disease, thereby opening the door to potential treatment of the degenerative neurological disorder that is the fourth leading cause of death in the United States.

The scientists have shown for the first time in live animals that accumulation of a common brain protein called beta-amyloid causes the nerve damage characteristic of Alzheimer’s disease and that it is possible to prevent such damage. At present, there is no good therapy for Alzheimer’s.

The report in today’s Proceedings of the National Academy of Sciences is but the most recent in a series of studies that have brought researchers very close to identifying the precise cause of the disorder and developing new therapies.

“Having the capacity to test potential treatments in animals represents a long-awaited victory in the battle against Alzheimer’s disease,” said neurologist Zevan Khachaturian of the National Institute on Aging.

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“We’re very excited about this and hope other people will follow up on it,” said neurologist Creighton Phelps of the Alzheimer’s Assn. “We’re getting right to the heart of the matter, that beta-amyloid seems to be playing a very key role in Alzheimer’s. We can’t say it’s the cause quite yet, but if we can block it, we may very well be able to slow down or stop the progression of the disease.”

Neurologist Bruce A. Yankner of Boston Children’s Hospital, the principal investigator in the new study, said members of the team are already studying the effects of the brain hormone, called substance P, in other animals, including primates, and that they could begin studying the material in humans within five years.

Alzheimer’s disease is characterized by memory loss, disorientation, depression and deterioration of bodily functions. According to the National Institute on Aging, it affects about 4 million Americans and causes 100,000 deaths annually. The average time between diagnosis and death is eight years.

The most noticeable biological sign of Alzheimer’s is the presence of protein plaques in the regions of the brain that control memory and learning. The primary component of these plaques, which are observable only upon an autopsy, is beta-amyloid.

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Neurologists have debated for years whether the plaques are the cause of Alzheimer’s or simply a byproduct of an unknown disease process. But a growing body of evidence is implicating the plaques as a cause.

Last fall, Yankner and molecular biologist Rachael Neve of UC Irvine independently reported that beta-amyloid caused the degeneration of brain cells grown in the laboratory. In April, biochemist Eugene Roberts of the City of Hope in Duarte reported that injections of beta-amyloid into the brains of mice caused the animals to forget tasks they had just learned.

Now Yankner and his colleagues at Massachusetts General Hospital and the University of Alaska have shown that injection of beta-amyloid into rat brains causes the death of cells near the injection site, seemingly closing the circle. The team, however, has not had time to study the effects of the injections on the animals’ behavior, a necessary step in proving that the protein causes the disorder.

That proof is expected to come from studies of two new strains of genetically engineered mice, reported last month, that develop beta-amyloid plaques in their brains. But those mice, which have now reached only middle age, have not been studied long enough to determine whether they develop mental impairment as a result of the plaque formation.

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But the most exciting and “most surprising” aspect of Yankner’s study, according to Phelps, is that the cell death caused by beta-amyloid can be blocked by injecting substance P into the brain along with the beta-amyloid or by injecting it into the bloodstream as much as 24 hours later.

Substance P is a small neurotransmitter, a compound that assists in the transfer of electrical signals between brain cells. Studies have shown that substance P and some other neurotransmitters are present in abnormally low concentrations in the brains of Alzheimer’s victims.

One of substance P’s principal roles is as a transmitter of pain impulses from the spinal cord to the brain. Because of that role, drug companies have done extensive studies of its pharmacology and of chemicals that can alter its activity in the hopes of discovering new pain relievers.

“But to the best of my knowledge, substance P has never been administered to humans,” Yankner said, so nothing is known about its potential side effects. Consequently, it will have to be studied in primates and other animals before it can be submitted for human trials.

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But that large body of research already conducted, he added, should speed the search for drugs that could mimic its biological activity and thereby block brain cell degeneration. One or more of those drugs could be cheaper or more effective than substance P itself.


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