A high-throughput screen to identify inhibitors of amyloid β-protein precursor processing

被引:25
作者
Bakshi, P
Liao, YF
Gao, J
Ni, J
Stein, R
Yeh, LA
Wolfe, MS
机构
[1] Harvard Univ, Brigham & Womens Hosp, Ctr Neurol Dis, Dept Neurol,Sch Med, Boston, MA 02115 USA
[2] Brigham & Womens Hosp, Lab Drug Discovery Neurodegenerat, Boston, MA 02115 USA
[3] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
Alzheimer's disease; high-throughput screening; luciferase; amyloid; gamma-secretase;
D O I
10.1177/1087057104270068
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
Cerebral accumulation of the amyloid beta-peptide (Abeta) is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Because Abeta is produced from the proteolysis of amyloid beta-protein precursor (APP) by beta- and gamma-secretases, these enzymes are considered important drug targets for AD. The authors have developed a luciferase-based reporter system that can identify new molecules that inhibit APP processing in a high-throughput manner. Such molecules can help in understanding the biology of APP and APP processing and in developing new drug prototypes for AD. In this system, APP is fused on its C-terminus with Gal4-VP16, a chimeric yeast-viral transcription activator, and luciferase is under control of the yeast Gal4 promoter. Compounds that modulate the luciferase signal may affect the secretases directly, interact with modifiers of these proteases, or interact with APP directly. The authors successfully interfaced this assay with a high-throughput screen, testing similar to60,000 compounds with diverse chemical structures. In principle, this sensitive, specific, and quantitative assay may be useful for identifying both inhibitors and stimulators of APP processing.
引用
收藏
页码:1 / 12
页数:12
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