Trigger for Alzheimer's is discovered

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Trigger for Alzheimer's is discovered

© St. sburg Times

October 22, 1999

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The long, brutal process that leads to Alzheimer's disease starts when a

single enzyme snips a protein that protrudes from brain cells, leading to

the release of toxic shards. Now scientists report that they have found that

enzyme, opening the door to the development of drugs that might block it

and, if the drugs prove safe, prevent or slow the disease.

The discovery of the enzyme had eluded scientists at universities and drug

companies for more than a decade, though they had given it a name,

beta-secretase. So many false claims of discovery were announced that

investigators automatically doubted anyone who claimed to have found it.

But experts say the new work, by Dr. Citron and his colleagues at

Amgen, a California biotechnology company, is different -- that it passes

crucial tests of authenticity, convincing even some skeptics. The report

appears in today's issue of the journal Science.

Blocking the enzyme, scientists say, might prevent the progress of the

disease in the same way that reducing cholesterol has been shown to blunt

the ravages of heart disease.

Dr. Sangram Sisodia, chairman of the department of neurobiology,

pharmacology and physiology at the University of Chicago, said that when he

first heard of the Amgen result, he dismissed it, saying: " It's junk. It has

been junk after junk for 12 years. " But, he said, " When I read the paper, I

was overwhelmed. The set of experiments in this paper was a tour de force. "

His enthusiasm was shared by other scientists, also not connected with the

study. " We now have a target, an identified target for drug development, "

said Dr. Rudolph Tanzi, a professor of neurology at Harvard Medical School

and the Massachusetts General Hospital.

The hope, Citron said, is that such a drug might stop the progress of

Alzheimer's disease in a person who has it, or even prevent it in those

likely to develop it. Still, Citron and other scientists emphasized that the

development of a drug was years away and that its success could not be

predicted.

" Obviously this does not translate into a treatment tomorrow, " Citron said.

" But it is a good start. "

With the beta-secretase discovery, several scientists said, the field of

Alzheimer's research is poised at the same place as AIDS research several

years ago, when scientists discovered that the AIDS virus needed a

protease -- an enzyme that cuts protein -- to replicate.

Drug companies seized on that discovery, searching for compounds to block

the HIV protease. Now protease inhibitors are on the market and are a vital

part of AIDS therapy. Beta-secretase is also a protease, and its method of

cutting is similar to the method of the HIV protease.

" With beta-secretase, the field of Alzheimer's research has now been granted

the same opportunity that AIDS researchers were granted, " Tanzi said.

Dr. Norman Relkin, an Alzheimer's specialist at the Weill-Cornell Medical

Center in New York, said there was no doubt about the potential unleashed by

the discovery. " This is one of the long-sought-after Holy Grails of

Alzheimer's research, " he said.

In Alzheimer's disease, brain cells die, slowly and inexorably. And as

patients' minds decay, areas of their brains that control memory and

reasoning and judgment are covered with an accumulation of microscopic balls

of debris, known as amyloid, mostly made up of aggregations of a protein

fragment called A beta.

" Most of us, and most of the big pharmaceutical companies, agree that if you

figure out a way of getting rid of amyloid, you will have a good drug for

Alzheimer's disease, " Tanzi said.

Over the years, scientists have learned that A beta is a small piece of a

much larger protein that protrudes from cells. It can be created when the

beta-secretase clips the protein in two and then another enzyme,

gamma-secretase, snips the resulting protein fragments, creating one piece

that is the toxic A beta protein and another that is a harmless piece of

protein debris.

In theory, scientists could stop A beta production by blocking either the

beta- or the gamma-secretase. But both enzymes were elusive. " The problem is

that there are multiple proteases, and in making cell extracts, you release

all of the proteases, " Citron said. " It is very hard to sort out which are

relevant. "

Several large drug companies decided to go ahead anyway, even without the

beta-secretase or the gamma-secretase in hand. Instead, they studied cells

in the laboratory that released A beta protein and looked for drugs that

would prevent the substance from being released.

Citron and his colleagues decided to take a different tack -- to look for

the gene that directs cells to make beta-secretase. In a long and tedious

set of experiments that began in 1997, they began a process of progressive

elimination, searching first for a string of about 100 genes that contained

the one they wanted, then narrowing the gene strings down to batches of 20

and, finally, homing in on the gene. With the gene in hand, they could use

it to make the enzyme and show that the enzyme cut the large precursor

protein at exactly the right spot and at no other spot.

Amgen is now looking for compounds that can block the beta secretase.

Relkin, of the Weill-Cornell center, said it was impossible to predict how

soon such a drug could be developed. But he added, " It is certainly exciting

to be able to ask these questions. "

-- Information from the Los Angeles Times was used in this report.