3 July 2000. Results presented by three research groups this week all confirm
that presenilin is, at the least, essential for γ-secretase to cleave amyloid
precursor protein in the process that release amyloid-β. In fact, say these
authors, the results leave little doubt that presenilin IS the γ-secretase.
In the July issue of Nature Cell Biology, Bart De Strooper, An Herreman, and
colleagues confirm that either presenilin-1 or presenilin-2 is necessary for
γ-secretase cleavage of amyloid precursor protein (APP). This has been difficult
to demonstrate conclusively because mice whose genes are altered to eliminate
presenilin expression die early in embryogenesis. Using embryonic stem cells
the researchers were able to show that the absence of both presenilins eliminates
all γ-secretase activity. This point was reinforced by Bruce Yankner, Zhuohua
Zhang, and colleagues, who showed that presenilins were required for γ-secretase
cleavage in blastocyst cultures. Also in this issue of Nature Cell Biology,
Dennis Selkoe, Michael Wolfe, William Esler, and colleagues replicate recent
results from Steven Gardell and his group at Merck,
showing that drugs designed to bind γ-secretase at its APP-binding site
wind up fishing presenilin out of the petri dish.
This spate of circumstantial evidence makes a stronger case for presenilin
being γ-secretase, though all three groups are careful to say that presenilin
could still be helping the real γ-secretase, and as Wolfe's group writes,
"Unequivocal certainty ... must await the identification of other essential
cofactors, subsequent reconstitution of proteolytic activity, and detailed structural
studies with enzyme-inhibitor complexes." [For more detail on this requirement,
see Sam Sisodia's comments in our news item below on the Gardell et al. paper.]
Still, Wolfe's group feels comfortable stating that this new evidence "makes
it all but certain that presenilins contain the active site of γ-secretase."-Hakon
Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Nature Cell Bio 2000;2:461-2. Abstract
Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. Nature Cell Bio 2000;2:463-65. Abstract
Esler W, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. Transition-state analogue inhibitors of γ-secretase bind directly to
presenilin-1. Nature Cell Bio 2000 Jul;2:428-34. Abstract
See also De Strooper B. Alzheimer's disease. Closing in on γ-secretase.
Nature. 2000 June 8;405:627-8 Abstract
for a discussion of these results.