Scientists have found a new member of a gang of proteins that attack the brain to cause Alzheimer's disease. The new protein helps prepare one of the raw materials that builds up in amyloid plaques. Identifying it, researchers say, opens up a new target for drugs that stop the disease.
Alzheimer's afflicts about 4 million people in the United States, leaving them disoriented, forgetful, and increasingly unable to take care of themselves. The neurological damage seems to result from deposits in the brain called amyloid plaques. One of the main ingredients in these plaques, a peptide called beta amyloid, is created when enzymes cut up a protein called APP. Some of the cellular scissors that snip out beta amyloid are a group of enzymes called the presenilins (see Science, 22 October 1999, p. 650), but scientists know the presenilins have help.
To find one of these accomplices, a research team led by neurobiologist Gang Yu of the University of Toronto looked for proteins that hang out with presenilins. The researchers isolated presenilin-1 from Alzheimer's-like cells and discovered a new protein they dubbed nicastrin. It appeared to have the strong grip necessary for a cutting enzyme: When Yu and his team grabbed onto nicastrin, APP came along for the ride. And more direct evidence for its role in making plaques is the fact that cells produced more beta amyloid if they contained certain mutated forms of nicastrin, the researchers report in the 7 September issue of Nature. They suggest that nicastrin and presenilin-1 are members of a large complex they call a secretosome in which many proteins collaborate to make beta amyloid.
Nicastrin is "an important piece of the puzzle" says molecular neurologist Sangram Sisodia of the University of Chicago. Though it's clear that nicastrin is part of the machine that makes the beta amyloid peptide, he says, it's not clear what it does. It might cut APP itself, or it might assist presenilin or other proteins in the task. Figuring out these details, says Sisodia, will guide the design of drugs that might slow the progression of Alzheimer's.
The Alzheimer Research Forum