The inhibition of γ-secretase as a therapeutic approach to Alzheimer's disease

被引：26

作者：

Tomita, T ^{[1
]}

Iwatsubo, T ^{[1
]}

机构：

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

来源：

DRUG NEWS & PERSPECTIVES | 2004年 / 17卷 / 05期

关键词：

D O I：

10.1358/dnp.2004.17.5.829036

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Alzheimer's disease is a dementing neurodegenerative disorder for which there is no effective treatment at present. Genetic and biological studies provide evidence that the production and deposition of amyloid-beta peptides (Abeta) contribute to the etiology of Alzheimer's disease. gamma-Secretase is the pivotal enzyme in generating the C terminus of Abeta, which determines its aggregability and speed of deposition. Drugs that regulate the production of Abeta by inhibiting gamma-secretase activity could provide an effective therapy for Alzheimer's disease, although recent studies suggest that gamma-secretase plays important roles in cellular signaling. This review focuses on studies of the gamma-secretase biology and provides the direction for developing effective and selective gamma-secretase inhibitors as drugs for the treatment of Alzheimer's disease. (C) 2004 Prous Science. All rights reserved.

引用

收藏

页码：321 / 325

页数：5

相关论文

共 33 条

[11] 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

[12] Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease [J].

in 't Veld, BA ;

Ruitenberg, A ;

Hofman, A ;

Launer, LJ ;

van Duijn, CM ;

Stijnen, T ;

Breteler, MMB ;

Stricker, BHC .

NEW ENGLAND JOURNAL OF MEDICINE, 2001, 345 (21) :1515-1521

[13] γ-secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2 [J].

Kimberly, WT ;

LaVoie, MJ ;

Ostaszewski, BL ;

Ye, WJ ;

Wolfe, MS ;

Selkoe, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (11) :6382-6387

[14] The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice [J].

Lanz, TA ;

Himes, CS ;

Pallante, G ;

Adams, L ;

Yamazaki, S ;

Amore, B ;

Merchant, KM .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 305 (03) :864-871

[15] Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1 [J].

Li, YM ;

Xu, M ;

Lai, MT ;

Huang, Q ;

Castro, JL ;

DiMuzio-Mower, J ;

Harrison, T ;

Lellis, C ;

Nadin, JL ;

Neduvelil, JG ;

Register, RB ;

Sardana, MK ;

Shearman, MS ;

Smith, AL ;

Shi, XP ;

Yin, KC ;

Shafer, JA ;

Gardell, SJ .

NATURE, 2000, 405 (6787) :689-694

[16] Selective inhibition of Aβ42 production by NSAID R-enantiomers [J].

Morihara, T ;

Chu, T ;

Ubeda, O ;

Beech, W ;

Cole, GM .

JOURNAL OF NEUROCHEMISTRY, 2002, 83 (04) :1009-1012

[17]

NETZER WJ, IN PRESS P NATL ACAD

[18] Presenilins mediate a dual intramembranous γ-secretase cleavage of Notch-1 [J].

Okochi, M ;

Steiner, H ;

Fukumori, A ;

Tanii, H ;

Tomita, T ;

Tanaka, T ;

Iwatsubo, T ;

Kudo, T ;

Takeda, M ;

Haass, C .

EMBO JOURNAL, 2002, 21 (20) :5408-5416

[19] New protease inhibitors prevent γ-secretase-mediated production of Aβ40/42 without affecting Notch cleavage [J].

Petit, A ;

Bihel, F ;

da Costa, CA ;

Pourquié, O ;

Checler, F ;

Kraus, JL .

NATURE CELL BIOLOGY, 2001, 3 (05) :507-511

[20] GSK-3α regulates production of Alzheimer's disease amyloid-β peptides [J].

Phiel, CJ ;

Wilson, CA ;

Lee, VMY ;

Klein, PS .

NATURE, 2003, 423 (6938) :435-439

← 1 2 3 4 →