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THE identification of an enzyme central to the progression of Alzheimer’s
disease could speed up the design of drugs for this devastating illness.

The brains of patients with Alzheimer’s tend to fill up with solid plaques of
the beta amyloid protein (Ab). In healthy people, the most common form of Ab is
40 amino acids long. But in Alzheimer’s, a form of Ab with 42 amino acids is
prevalent. So far, however, the secretase enzyme that snips Ab42 from a larger
precursor protein has remained elusive.

Now three groups in Belgium, the US and Canada have shown that, as some
researchers suspected, the long-sought enzyme comes from the presenilin
gene—the very gene most often altered in familial Alzheimer’s disease.
“The identity of this secretase has plagued the Alzheimer’s field for a long
time,” says Michael Wolfe of Brigham and Women’s Hospital in Boston, who led one
of the teams.

Wolfe and his colleagues established the link by designing a molecule, based
on the structure of Ab42, that they knew should stick to the active site of the
secretase. Sure enough, they found it stuck tightly to the presenilin protein.
Wolfe believes that in familial Alzheimer’s, presenilin is overactive, churning
out much more Ab42 than normal.

In theory, compounds such as Wolfe’s could work as drugs that block the
secretase and prevent Ab42 being formed, but they will need to be designed to
work in the body. “Designing drugs that work on presenilin has been
scattershot,” Wolfe says. “This will make it more like using a rifle with a
telescopic sight.”

Virginia Lee of the University of Pennsylvania in Philadelphia, who is
helping to design a stain for Ab that can light up plaque in living brains, says
the finding is good news. “It is encouraging. There could be a compound in the
future that could actually reduce amyloid burden.”