A beta deposition inhibitor screen using synthetic amyloid

被引:75
作者
Esler, WP
Stimson, ER
Ghilardi, JR
Felix, AM
Lu, YA
Vinters, HV
Mantyh, PW
Maggio, JE
机构
[1] HARVARD UNIV,SCH MED,DEPT BIOL CHEM & MOL PHARMACOL,BOSTON,MA 02115
[2] UNIV MINNESOTA,VA MED CTR,MINNEAPOLIS,MN 55417
[3] UNIV MINNESOTA,DEPT PSYCHIAT,MINNEAPOLIS,MN 55417
[4] VANDERBILT UNIV,DEPT MICROBIOL & IMMUNOL,NASHVILLE,TN 37232
[5] WILLIAM PATERSON COLL NEW JERSEY,DEPT CHEM & PHYS,WAYNE,NJ 07470
[6] UNIV CALIF LOS ANGELES,DEPT PATHOL,LOS ANGELES,CA 90095
[7] UNIV CALIF LOS ANGELES,LAB MED,LOS ANGELES,CA 90095
关键词
Alzheimer's disease; A beta deposition; high-throughput screen; Congo red; structure-activity; ALZHEIMER-DISEASE; PRECURSOR PROTEIN; APOLIPOPROTEIN-E; TRANSGENIC MICE; PEPTIDE; AGGREGATION; INVITRO; PLAQUES;
D O I
10.1038/nbt0397-258
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The formation, growth, and maturation of brain amyloid ''senile'' plaques are essential pathological processes in Alzheimer's disease (AD) and key targets for therapeutic intervention, The process of in vitro deposition of A beta at physiological concentrations onto plaques in AD brain preparations has been well characterized, but is cumbersome for drug discovery. We describe here a high-throughput screen for inhibitors of A beta deposition onto a synthetic template (synthaloid) of fibrillar A beta immobilized in a polymer matrix. Synthaloid is indistinguishable from plaques in AD brain (the natural template) in deposition kinetics, pH profile, and structure-activity relationships for both A beta analogs and inhibitors, Synthaloid, in contrast to current A beta aggregation screens, accurately predicted inhibitor potency for A beta deposition onto AD cortex preparations, validating its use in searching for agents that can slow the progression of AD and exposing a previously inaccessible target for drug discovery.
引用
收藏
页码:258 / 263
页数:6
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