With this year’s Awards for Medical Research in Alzheimer’s Disease, the MetLife Foundation recognized three scientists who advanced knowledge of the β- and γ-secretase enzymes and in this way helped build a foundation for much of today’s worldwide drug development programs against Alzheimer disease. Bart de Strooper of the K.U. Leuven, Belgium, Robert Vassar of Northwestern University, Chicago, and Philip Wong of Johns Hopkins University School of Medicine in Baltimore, received the award at a scientific briefing and ceremony held February 29 in Washington, D.C.
The MetLife Foundation has supported AD research for more than 20 years, having awarded some $11 million in grants through its awards program and other activities. This prize has become a prestigious one in the field, and it comes with a $25,000 personal check and $175,000 for the scientists’ institutions.
Working independently, the three scientists each spent the last decade probing the molecular biology of the two Aβ-generating enzymes. The foundation cited De Strooper’s extensive research on the role of γ secretase in generating Aβ and in Notch signaling, as well as his group’s research on different versions of the γ-secretase complex, (see, e.g., De Strooper et al., 1998; De Strooper et al., 1999; Herreman et al., 2000; De Strooper, 2003; Dominguez et al., 2005). Vassar was recognized for being first to clone the β-secretase BACE, and for his group’s subsequent work generating BACE-deficient mouse strains, characterizing BACE, and validating it as a drug target (Vassar et al., 1999; Haniu et al., 2000; Luo et al., 2001; Ohno et al., 2004). Last but not least, Wong early on recognized the role of presenilin in Notch signaling during development, and the need to inhibit the γ-secretase complex delicately, so as to spare Notch. To that end, Wong created a series of mouse models with each of the γ-secretase components deleted. Roughly simultaneously with Vassar, Wong made the first set of BACE knockout strains that validated BACE as a drug target (Cai et al., 2001; Li et al., 2003; Ma et al., 2005; Li et al., 2007).
De Strooper and Vassar are past members of the ARF Scientific Advisory Board, and all three scientists contribute to the Alzforum. On behalf of the community, the ARF editors lift an imaginary glass of bubbly to the awardees. Congratulations!—Gabrielle Strobel.
Image Listing with Navigation Citations
- De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998 Jan 22;391(6665):387-90. PubMed.
- De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22. 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.
- De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex. Neuron. 2003 Apr 10;38(1):9-12. PubMed.
- Dominguez D, Tournoy J, Hartmann D, Huth T, Cryns K, Deforce S, Serneels L, Camacho IE, Marjaux E, Craessaerts K, Roebroek AJ, Schwake M, D'Hooge R, Bach P, Kalinke U, Moechars D, Alzheimer C, Reiss K, Saftig P, De Strooper B. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J Biol Chem. 2005 Sep 2;280(35):30797-806. PubMed.
- Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999 Oct 22;286(5440):735-41. PubMed.
- Haniu M, Denis P, Young Y, Mendiaz EA, Fuller J, Hui JO, Bennett BD, Kahn S, Ross S, Burgess T, Katta V, Rogers G, Vassar R, Citron M. Characterization of Alzheimer's beta -secretase protein BACE. A pepsin family member with unusual properties. J Biol Chem. 2000 Jul 14;275(28):21099-106. PubMed.
- Luo Y, Bolon B, Kahn S, Bennett BD, Babu-Khan S, Denis P, Fan W, Kha H, Zhang J, Gong Y, Martin L, Louis JC, Yan Q, Richards WG, Citron M, Vassar R. Mice deficient in BACE1, the Alzheimer's beta-secretase, have normal phenotype and abolished beta-amyloid generation. Nat Neurosci. 2001 Mar;4(3):231-2. PubMed.
- Ohno M, Sametsky EA, Younkin LH, Oakley H, Younkin SG, Citron M, Vassar R, Disterhoft JF. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron. 2004 Jan 8;41(1):27-33. PubMed.
- Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci. 2001 Mar;4(3):233-4. PubMed.
- Li T, Ma G, Cai H, Price DL, Wong PC. Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals. J Neurosci. 2003 Apr 15;23(8):3272-7. PubMed.
- Ma G, Li T, Price DL, Wong PC. APH-1a is the principal mammalian APH-1 isoform present in gamma-secretase complexes during embryonic development. J Neurosci. 2005 Jan 5;25(1):192-8. PubMed.
- Li T, Wen H, Brayton C, Laird FM, Ma G, Peng S, Placanica L, Wu TC, Crain BJ, Price DL, Eberhart CG, Wong PC. Moderate reduction of gamma-secretase attenuates amyloid burden and limits mechanism-based liabilities. J Neurosci. 2007 Oct 3;27(40):10849-59. PubMed.