Enzyme Points Way to Alzheimer's Therapies

Researchers are making new strides in one of the most frustrating of medical science's battles, the war against Alzheimer's disease. In this week's Science (21 October, p. 735) a team from the biotech company Amgen Inc. in Thousand Oaks, California, reports finding an enzyme called b-secretase, which has long been suspected of playing a key role in the development of the disease. The enzyme may become a new target for drugs that can slow or even reverse Alzheimer's course.

b-secretase acts like a pair of molecular scissors, snipping a piece off a large protein to produce b-amyloid, a smaller protein that builds up in plaques in the brains of Alzheimer's patients and is thought to kill neurons. Over the last 5 years, at least a dozen teams have reported nailing down the elusive b-secretase, but none have swayed the Alzheimer's research community and many have already failed to stand the test of time. But the one identified by the Amgen team "is incontrovertible," comments Sangram Sisodia, a b-amyloid specialist at the University of Chicago. "I was floored by the data."

The researchers, led by molecular biologists Martin Citron and Robert Vassar, found a protein, called BACE, which proved to have all the properties expected in a b-secretase. For example, antibody studies showed that it is located in the Golgi apparatus and endosomes, two structures within cells in which b-amyloid is known to be cleaved from its large precursor protein. In addition, the Amgen team showed that inhibiting the cellular enzyme decreases b-amyloid production by cultured cells.

But the Amgen enzyme is not the only b-secretase candidate. Elan Pharmaceuticals in South San Francisco has a patent on another molecule, which is apparently different from Amgen's, and pharmaceutical giant SmithKline Beecham is known to have yet another candidate. Both companies intend to report their findings at next week's annual meeting of the Society for Neuroscience in Miami. Researchers believe that there could be more than one version of the enzyme.

Even before they knew the actual identity of (-secretase, drug companies had already been developing compounds that block the enzyme's activity; but now that researchers have actual secretase enzymes in hand, they can look for more specific and powerful inhibitors.

Whether this strategy will stop Alzheimer's disease in its tracks is a big if, however, because there's still a debate over whether the b-amyloid deposited in plaques causes the brain damage seen in Alzheimer's disease, or instead is a symptom of some other underlying factor. The new enzymes could settle the dispute, if inhibiting them does in fact help Alzheimer's patients. "Finding the b-secretase enzyme is a very important development, not only for drug development but also for the clues it will give us about [amyloid] biology," says John Durkin, a biochemist at Cephalon in West Chester, Pennsylvania.