In Aid Of Memory 

Researchers have pinned down the 

enzymes that cause Alzheimer's, reports Biplab Das 

Kamolendu Bose, a senior executive of 56, had a sharp memory. One day, on his way to office, he suddenly forgot where he was heading for. Although that day Bose somehow reached his office, a few months later, his memory began to fail more frequently. After a couple of years, Bose's memory had deteriorated to a great extent. A thorough check-up unveiled the secret - Bose was the victim of Alzheimer's disease. 

In patients like Bose, tiny plaques of a small protein called beta-amyloid build up in the brains. This protein deposition destroys neurons, the cells that are responsible for transmission of impulses. With the demise of these cells, communication through neural pathways gets jeopardised resulting in memory loss. 

So far, researchers knew that isolating the amyloid producer might be the key component for a novel therapy. Half a decade ago an elusive enzyme called beta-secretase was found. This enzyme is supposed to release beta-amyloid from its larger precursor protein body known as APP (amyloid precursor protein). As the protein breaks from the main body, it deposits on neurons as plaques. 

Despite getting their hands on beta-secretase, the Alzheimer's researchers around the world so far failed to detect the specific beta-secreatse enzyme, directly related to amyloid protein. 

In a recent issue Science, a research team led by Martin Citron and Robert Vassar at the biotech company Amgen Inc in Thousands Oaks, California, is reported to have closed in on an enzyme very similar to beta-secretase. The protein that researchers called betasite APP cleaving enzyme (BACE) proved to have all the properties found in a beta-secretase. 

Other researchers identified another enzyme known as gamma-secretase. With these new enzymes in hand, researchers are ready to develop a drug that could slow or reverse the disease. 

To design a drug, researchers had to isolate the enzyme (BACE). But, looking for a specific protein-splitting enzyme is like finding a needle in haystack. The Amgen team abandoned the ploy to isolate the specific beta-secretase enzyme directly. Instead, the team looked for its gene. To do that, researchers introduced pools of cloned genes into cultured cells that make beta-amyloid protein. After repeated experiments, the research team zeroed in on a single gene that raised beta-amyloid production. 

Moreover, the Amgen team confirmed the sites - golgi apparatus and endosomes - inside a cell where APP is cleaved to free beta-amyloid. Furthermore, Citron and his colleagues showed that BACE cleaved APP at the right spot for a beta-secretase. Inhibiting this cellular enzyme reduced beta-amyloid production by cultured cells. "Now they have both cell biological evidence and evidence that the purified enzyme acts with the right specificity," says De Stopper, a neuroscientist at Catholic University in Leuven, Belgium. 

This year, in an issue of Nature, Harvard neurobiologist Dennis Selkoe and his colleagues were reported to have found a protein called presenilin 1, one of the two related proteins implicated in Alzheimer's disease. A few days later Selkoe and his team found the other - presenilin-2. Both these presenilin proteins are right candidates for gamma-secretase, the second enzyme that frees beta-amyloid from APP. 

With this knowledge of actual secretase enzymes, researchers hope to develop more specific and powerful inhibitors. According to Alzheimer's researchers, such inhibitors will not only stifle the formation of new plaques but also mop up the existing ones.