A common interest in the uncanny features of the amyloid precursor protein (APP)-clipping enzyme γ-secretase has fueled years of productive rivalry between Takeshi Iwatsubo of the University of Tokyo and Michael Wolfe of Brigham and Women’s Hospital in Boston. Yesterday, the two scientists shared the stage as recipients of the 2009 MetLife Foundation Awards for Medical Research in Alzheimer’s Disease. “We have been competitors—but friendly competitors, with an emphasis on ‘friendly,’” Wolfe said during the scientific briefing preceding the MetLife awards luncheon held 18 February in Washington, D.C. Founded in 1986 to bolster basic research in AD, the MetLife Foundation offered each winner $200,000 in research money and a $50,000 personal check.
The foundation recognized Iwatsubo for his histopathological and biochemical studies of postmortem AD brains, which have helped establish cellular and genetic models to dissect key steps of the neurodegenerative process. The postmortem studies extended biochemical research published in the early 1990s suggesting that “very subtle differences in the tail length of Aβ proteins determine their tendency to aggregate and form amyloid plaques,” Iwatsubo said at the MetLife briefing. “As a clinical neurologist and pathologist, I wanted to see what happened to Aβ40 and Aβ42 in the brains of patients with Alzheimer’s,” Iwatsubo said. Since then, he, together with Wolfe and others, has helped identify presenilin as the business end of the γ-secretase complex (Schroeter et al., 2003) that generates Aβ in vivo, and has provided insight into the role of presenilin cofactors in γ-secretase function (Takasugi et al., 2003). These days, Iwatsubo’s group is among several that steer the ongoing quest to solve γ-secretase’s crystal structure (see ARF related news story).
Wolfe, a trained chemist, has taken a different tack to address γ-secretase structure and function—by developing inhibitors that block its cleavage of amyloid precursor protein (APP). “I liken these compounds to probes that are sent out to give us info we cannot see or feel for ourselves,” Wolfe said at the MetLife briefing. However, given presenilin’s vital role in cell fate decisions across a variety of organisms, “we cannot simply block this enzyme,” he said. “We now know that we must develop compounds that tweak γ-secretase, not shut it down—that lower its Aβ function but leave the other parts intact.” Toward that end, a multinational team that included Wolfe reported last year that certain compounds may stymie γ-secretase activity without directly contacting the enzyme but instead by binding APP (Kukar et al., 2008 and ARF related news story). Wolfe’s group has also developed an RNA antisense approach to suppress BACE1, the enzyme that delivers the initiating cut in the sequential cleavage of Aβ from APP (Mowrer and Wolfe, 2008 and ARF related news story).
Iwatsubo has served on ARF’s Scientific Advisory Board, and both he and Wolfe contribute to the Alzforum. On behalf of the community, the ARF team congratulates this year’s MetLife winners!—Esther Landhuis.
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- Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13075-80. PubMed.
- Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. The role of presenilin cofactors in the gamma-secretase complex. Nature. 2003 Mar 27;422(6930):438-41. PubMed.
- Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, Moore B, Rangachari V, Cusack B, Eriksen J, Jansen-West K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe MS, Schmidt B, Walsh DM, Koo EH, Golde TE. Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12;453(7197):925-9. PubMed.
- Mowrer KR, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid beta-peptide production. J Biol Chem. 2008 Jul 4;283(27):18694-701. PubMed.