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 Heimer
- Brown PJ, Devanand DP, Liu X, Caccappolo E, . Functional impairment in elderly patients with mild cognitive impairment and mild Alzheimer disease. Arch Gen Psychiatry. 2011 Jun;68(6):617-26. PubMed.
- Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol. 2000 Jul;2(7):461-2. PubMed.
- Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol. 2000 Jul;2(7):428-34. PubMed.
- De Strooper B. Alzheimer's disease. Closing in on gamma-secretase. Nature. 2000 Jun 8;405(6787):627, 629. PubMed.
- Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, Yankner BA. Presenilins are required for gamma-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol. 2000 Jul;2(7):463-5. PubMed.