Sulindac sulfide is a noncompetitive γ-secretase inhibitor that preferentially reduces Aβ42 generation

被引：174

作者：

Takahashi, Y

Hayashi, I

Tominari, Y

Rikimaru, K

Morohashi, Y

Kan, T

Natsugari, H

Fukuyama, T

Tomita, T

Iwatsubo, T

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan

[2] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Synthet Nat Prod Chem, Bunkyo Ku, Tokyo 1130033, Japan

[3] Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Rat Med Sci, Bunkyo Ku, Tokyo 1130033, Japan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2003年 / 278卷 / 20期

关键词：

D O I：

10.1074/jbc.M301619200

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been known to reduce risk for Alzheimer's disease. In addition to the anti-inflammatory effects of NSAIDs to block cylooxygenase, it has been shown recently that a subset of NSAIDs selectively inhibits the secretion of highly amyloidogenic Abeta42 from cultured cells, although the molecular target(s) of NSAIDs in reducing the activity of gamma-secretase for Abeta42 generation (gamma(42)-secretase) still remain unknown. Here we show that sulindac sulfide (SSide) directly acts on gamma-secretase and preferentially inhibits the gamma(42)-secretase activity derived from the 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate-solubilized membrane fractions of HeLa cells, in an in vitro gamma-secretase assay using recombinant amyloid beta precursor protein C100 as a substrate. SSide also inhibits activities for the generation of Abeta40 as well as for Notch intracellular domain at higher concentrations. Notably, SSide displayed linear noncompetitive inhibition profiles for gamma(42)-secretase in vitro. Our data suggest that SSide is a direct inhibitor of gamma-secretase that preferentially affects the gamma(42)-secretase activity.

引用

页码：18664 / 18670

页数：7

共 46 条

[1] Inflammation and Alzheimer's disease [J].

Akiyama, H ;

Barger, S ;

Barnum, S ;

Bradt, B ;

Bauer, J ;

Cole, GM ;

Cooper, NR ;

Eikelenboom, P ;

Emmerling, M ;

Fiebich, BL ;

Finch, CE ;

Frautschy, S ;

Griffin, WST ;

Hampel, H ;

Hull, M ;

Landreth, G ;

Lue, LF ;

Mrak, R ;

Mackenzie, IR ;

McGeer, PL ;

O'Banion, MK ;

Pachter, J ;

Pasinetti, G ;

Plata-Salaman, C ;

Rogers, J ;

Rydel, R ;

Shen, Y ;

Streit, W ;

Strohmeyer, R ;

Tooyoma, I ;

Van Muiswinkel, FL ;

Veerhuis, R ;

Walker, D ;

Webster, S ;

Wegrzyniak, B ;

Wenk, G ;

Wyss-Coray, T .

NEUROBIOLOGY OF AGING, 2000, 21 (03) :383-421

[2] Presenilin-dependent γ-secretase activity modulates thymocyte development [J].

Doerfler, P ;

Shearman, MS ;

Perlmutter, RM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (16) :9312-9317

[3] Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].

Dovey, HF ;

John, V ;

Anderson, JP ;

Chen, LZ ;

Andrieu, PD ;

Fang, LY ;

Freedman, SB ;

Folmer, B ;

Goldbach, E ;

Holsztynska, EJ ;

Hu, KL ;

Johnson-Wood, KL ;

Kennedy, SL ;

Kholedenko, D ;

Knops, JE ;

Latimer, LH ;

Lee, M ;

Liao, Z ;

Lieberburg, IM ;

Motter, RN ;

Mutter, LC ;

Nietz, J ;

Quinn, KP ;

Sacchi, KL ;

Seubert, PA ;

Shopp, GM ;

Thorsett, ED ;

Tung, JS ;

Wu, J ;

Yang, S ;

Yin, CT ;

Schenk, DB ;

May, PC ;

Altstiel, LD ;

Bender, MH ;

Boggs, LN ;

Britton, TC ;

Clemens, JC ;

Czilli, DL ;

Dieckman-McGinty, DK ;

Droste, JJ ;

Fuson, KS ;

Gitter, BD ;

Hyslop, PA ;

Johnstone, EM ;

Li, WY ;

Little, SP ;

Mabry, TE ;

Miller, FD ;

Ni, B .

JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181

[4] Rank-order of potencies for inhibition of the secretion of Aβ40 and Aβ42 suggests that both are generated by a single γ-secretase [J].

Durkin, JT ;

Murthy, S ;

Husten, EJ ;

Trusko, SP ;

Savage, MJ ;

Rotella, DP ;

Greenberg, BD ;

Siman, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (29) :20499-20504

[5] Amyloid-lowering isocoumarins are not direct inhibitors of γ-secretase [J].

Esler, WP ;

Das, C ;

Campbell, WA ;

Kimberly, WT ;

Kornilova, AY ;

Diehl, TS ;

Ye, WJ ;

Ostaszewski, BL ;

Xia, WM ;

Selkoe, DJ ;

Wolfe, MS .

NATURE CELL BIOLOGY, 2002, 4 (05) :E110-E111

[6] Activity-dependent isolation of the presenilin-γ-secretase complex reveals nicastrin and a γ substrate [J].

Esler, WP ;

Kimberly, WT ;

Ostaszewski, BL ;

Ye, WJ ;

Diehl, TS ;

Selkoe, DJ ;

Wolfe, MS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (05) :2720-2725

[7] Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1 [J].

Esler, WP ;

Kimberly, WT ;

Ostaszewski, BL ;

Diehl, TS ;

Moore, CL ;

Tsai, JY ;

Rahmati, T ;

Xia, WM ;

Selkoe, DJ ;

Wolfe, MS .

NATURE CELL BIOLOGY, 2000, 2 (07) :428-434

[8] γ-secretase-mediated proteolysis in cell-surface-receptor signalling [J].

Fortini, ME .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2002, 3 (09) :673-684

[9] Alzheimer disease γ-secretase:: a complex story of GxGD-type presenilin proteases [J].

Haass, C ;

Steiner, H .

TRENDS IN CELL BIOLOGY, 2002, 12 (12) :556-562

[10] γ-secretase inhibitors repress thymocyte development [J].

Hadland, BK ;

Manley, NR ;

Su, DM ;

Longmore, GD ;

Moore, CL ;

Wolfe, MS ;

Schroeter, EH ;

Kopan, R .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (13) :7487-7491

← 1 2 3 4 5 →