Controversies drive Alzheimer’s disease research. Does the buildup in the brain of a protein fragment called beta-amyloid cause the illness, or is a protein known as tau the guilty molecule?
Does a gene somewhere on chromosome 12 play a role in the brain disorder? One simmering debate concerns the identity of enzymes, dubbed gamma-secretases, that perform the final cut on amyloid precursor protein (APP) to make beta-amyloid. Several new studies, reported in the June 8 Nature and July Nature Cell Biology, strengthen a theory that two molecules previously implicated in Alzheimer’s disease, called presenilins, are gamma-secretases.
“It’s no longer possibly true. It’s probably true,” contends Michael S. Wolfe of Harvard Medical School and Brigham and Women’s Hospital, both in Boston, an author of one of the studies.
Scientists skeptical that the presenilins are gamma-secretases remain unpersuaded by the new data but acknowledge the tide has turned. “All the data converge and put presenilins at the site of gamma-secretase activity,” admits Todd E. Golde of the Mayo Clinic in Jacksonville, Fla. “The only way we disprove the hypothesis is to find something else” that’s the APP-cutting enzyme.
Both camps want to resolve this issue because inhibiting gamma-secretase may offer a way to stop beta-amyloid accumulation and thereby prevent or slow development of Alzheimer’s disease. In fact, Bristol-Myers Squibb has already begun testing the safety of one such inhibitor in healthy people.
The notion that the presenilins are APP-cutting enzymes has appeal because mutations in the two genes encoding them predispose people to early-onset Alzheimer’s disease (SN: 8/19/95, p. 118). Yet the presenilins, which crisscross a cell membrane multiple times, don’t look like most enzymes that carve up proteins. These so-called proteases are usually much smaller and don’t inhabit cell walls.
“If there continues to be some skepticism, that’s the root of it,” remarks Stephen J. Gardell of Merck Research Laboratories in West Point, Pa.
In two of the new studies, groups led by Gardell and Wolfe independently report that compounds that inhibit gamma-secretase activity appear to target the presenilins. In the Nature paper, for example, Gardell’s team describes identifying gamma-secretase inhibitors and adding light-activated chemical groups to them. By mixing these compounds with a solution having gamma-secretase activity and shining light on it, the researchers hoped to force the inhibitors to permanently latch onto their target molecules. The inhibitors ended up joined to a presenilin.
“The biochemical evidence is extremely compelling,” says Gardell. But not conclusive, say investigators who note that a large molecular complex, which includes presenilin, is involved in gamma-secretase activity. The inhibitors used by Wolfe’s and Gardell’s teams may thwart a gamma-secretase within the complex and bind to neighboring presenilins, they maintain.
“The other interpretation [of the new data] is that presenilin-1 is pretty close to the gamma-secretase,” says Sangram S. Sisodia of the University of Chicago. “I think identifying components of the complex is the next big challenge.” He suggests that presenilin merely activates another protein, the true gamma secretase, in the complex.
Golde agrees and notes that his group has identified an inhibitor of gamma-secretase activity that doesn’t seem to bind to the presenilins.
In any case, all the investigators stress that the testing of any gamma-secretase inhibitors on people should proceed cautiously since presenilins seem to play a role in processing other proteins, including one involved in blood-cell formation. Bristol-Myers Squibb says it expects to expand the testing of its gamma-secretase inhibitor to people with Alzheimer’s disease later this year.