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That same year, other research teams, including one led by Selkoe, created yet another stir. They zeroed in on the elusive enzymes that snip the beta-amyloid fragment from the precursor protein. "We had the paper, and now we had the scissors," says Selkoe. If he is right, one of those scissors, gamma secretase, may actually be the presenilin-1 protein. Whatever the true identity of gamma secretase turns out to be, pharmaceutical companies are rushing to develop drugs that block it. Bristol-Myers Squibb has already started safety tests of one such compound and hopes to expand its study soon.
Many questions remain. For one thing, researchers are worried that gamma secretase may perform vital functions in the brain and that blocking it could cause serious side effects. Also, no one knows whether strategies aimed at lowering levels of beta amyloid will have any impact on the course of Alzheimer's disease--though if the beta-amyloid hypothesis is right, they should. Selkoe and other Amyloid People now see the disease process as a biochemical cascade; the event that triggers the cascade, they believe, is the accumulation of beta amyloid.
In essence, the brain perceives microscopic shards of beta amyloid as foreign bodies, and primitive immune cells called microglia that serve as biological garbage collectors valiantly and continuously try to clear them away. The result is a state of chronic inflammation that progressively injures nearby nerve cells. Among the powerful weapons the brain's immune system brings to bear are oxygen-free radicals, which is one reason many think that antioxidants like vitamin E may be helpful.
Beyond that, things get murky. It's not yet clear, for example, when tau enters the picture. Up to now, most thought the tangles form much later than the plaques. But neuroscientist Peter Davies of Albert Einstein College of Medicine thinks this view will be proved wrong. He believes some still unidentified biochemical event precedes the formation of tangles and plaques, perhaps a malfunction in the machinery that puts proteins together. "The question from the therapeutic standpoint," he observes, "is, What's responsible for the symptoms of disease? What's killing the cells? Is it amyloid or tau?"
BEYOND BETA AMYLOID AND TAU
The key question we still need to resolve," muses neurogeneticist John Hardy of the Mayo Clinic in Jacksonville, Fla., "is, What is the relationship between beta amyloid and tau?" That is why Hardy and others are so excited by the new strain of transgenic mice that scientists are breeding. By crossing mice that develop tangles with mice that develop plaques, they should finally be able to provide scientists with a research tool they've sorely lacked: lab animals that closely approximate the disease in humans.
Over the next several years, researchers can be expected to bring into increasingly sharp focus the enormously complicated molecular pathway of which beta amyloid and tau are just the most visible signposts, and in so doing they are likely to reveal a raft of new opportunities for therapeutic intervention. For example, a change in shape appears to be what makes tau go bad. Last year Davies and Harvard's Dr. Kun Ping Lu announced that they had found an enzyme that seemed to restore tau to its proper configuration.