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Friday, October 22, 1999

Scientists Find Enzyme Linked to
Alzheimer's

By GINA KOLATA 

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 developing drugs that might block it
and, if the drugs prove safe, to preventing or slowing the
disease. 

The discovery of the enzyme had eluded teams of 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 victory were announced that investigators
automatically doubted anyone who claimed to have found it. 

But experts say that the new work, by Dr. Martin Citron
and his colleagues at Amgen, a biotechnology company in
Thousand Oaks, Calif., is different -- that it passes
crucial tests of authenticity, convincing even some
skeptics. The report appears on Friday in thejournal
Science. 

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 Dr. Sisodia added: "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 Massachusetts
General Hospital. 

The hope, Dr. 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, Dr. Citron and other scientists emphasized
that the development of a drug was still years away
and that its success could not be predicted. 

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 researchers discovered that the AIDS virus, 
H.I.V., needed a protease -- an enzyme that cuts 
protein -- to replicate. 

Drug companies seized on that discovery, searching
for compounds to block the H.I.V. 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 H.I.V. protease. 

"With beta-secretase, the field of Alzheimer's
research has now been granted the same opportunity
that AIDS researchers were granted," Dr. Tanzi said.
"This is as exciting for Alzheimer's research as the
 H.I.V. protease enzyme was for AIDS research." 

Dr. Norman Relkin, an Alzheimer's specialist at
the Weill Medical College of Cornell University
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," Dr. Relkin said. 

In Alzheimer's disease, brain cells die, slowly
and inexorably, as patients gradually lose their
memories, their judgment, their ability to balance
a checkbook or find their way around their neighborhoods
or even their own homes. And as patients' minds crumble,
areas of their brains that control memory, 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," Dr. Tanzi said. 

Over the years, scientists have learned that A beta
is a small piece of a much larger protein tha
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," Dr. Citron said, "is that there are
multiple proteases, and in making cell extracts,
you release all of the proteases. 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. 

Dr. 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 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. Dr. Citron cautioned that it
would be several years before a potential drug was
found and tested sufficiently in the laboratory and
in animals until the company was ready to initiate
tests with people. 

Weill's Dr. Relkin 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." 

Copyright 1999 The New York Times Company 
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Victoria Nordli cg