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article at: http://www.nytimes.com/ 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 -------------------------------------------- Victoria Nordli cg