Word: gammas
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...likelihood that they would cross over the blood-brain barrier. And all the while, they checked and rechecked to make sure that during this biochemical shuffling they did not lose the key property that made these particular molecules potentially so valuable: their ability to block the activity of gamma secretase, an enzyme thought to play a critical role in the development of Alzheimer's disease...
...seem sure to follow. In fact, not just Bristol-Myers Squibb but also Amgen, Elan Pharmaceuticals, Eli Lilly, Merck and SmithKline Beecham are racing to develop similar compounds. The reason? Over the past five years, an explosion of insights into the genetics of Alzheimer's has bolstered confidence that gamma secretase and a related enzyme called beta secretase are not innocent bystanders but rather are intimately involved in the disease process...
Alzheimer's disease, many experts are all but convinced, starts with the abnormal buildup of a protein known as beta amyloid. The chief constituent of the scarlike plaques found in the brain of Alzheimer's patients, beta amyloid is made by nerve cells when beta and gamma secretase execute a one-two snip that cuts a larger precursor protein into a shorter fragment. Sometimes the fragment is 40 units long, sometimes 42. The slightly longer variant, scientists have found, is directly toxic to nerve cells. Among other things, it appears to stimulate the release of oxygen free radicals, thereby setting...
...Gamma secretase emerged as an attractive target shortly after 1995, when scientists working with DNA donated by families prone to early-onset Alzheimer's disease finally succeeded in cloning two genes known as presenilin 1 and presenilin 2. In a series of experiments, researchers established that these genes exercised tight control over the activity of gamma secretase. They found that the particular mutations in the Alzheimer's-prone families not only increased the rate at which gamma secretase produces beta amyloid but also enhanced its penchant for making the more toxic version...
...which was cloned only in 1999, also provides drug designers with a target. Inside nerve cells it competes with a third enzyme known as alpha secretase, whose activity, some think, may help protect the brain against Alzheimer's disease. When alpha makes the first cut in the precursor protein, gamma secretase makes a second cut that produces not beta amyloid but an innocuous protein fragment known as p3. Elan and Pharmacia, based in Peapack, N.J., among others, are actively working to develop beta secretase inhibitors...