A Novel Inhibitor of Amyloid β (Aβ) Peptide Aggregation FROM HIGH THROUGHPUT SCREENING TO EFFICACY IN AN ANIMAL MODEL OF ALZHEIMER DISEASE

被引:91
作者
McKoy, Angela Fortner [1 ]
Chen, Jermont [1 ]
Schupbach, Trudi [2 ]
Hecht, Michael H. [1 ]
机构
[1] Princeton Univ, Dept Chem, Princeton, NJ 08544 USA
[2] Princeton Univ, Dept Mol Biol, Howard Hughes Med Inst, Princeton, NJ 08544 USA
基金
美国国家卫生研究院;
关键词
GINKGO-BILOBA; DROSOPHILA MODEL; PROTEIN; OLIGOMERS; TOXICITY; ASSAY;
D O I
10.1074/jbc.M112.348037
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
Compelling evidence indicates that aggregation of the amyloid beta (A beta) peptide is a major underlying molecular culprit in Alzheimer disease. Specifically, soluble oligomers of the 42-residue peptide (A beta 42) lead to a series of events that cause cellular dysfunction and neuronal death. Therefore, inhibiting A beta 42 aggregation may be an effective strategy for the prevention and/or treatment of disease. We describe the implementation of a high throughput screen for inhibitors of A beta 42 aggregation on a collection of 65,000 small molecules. Among several novel inhibitors isolated by the screen, compound D737 was most effective in inhibiting A beta 42 aggregation and reducing A beta 42-induced toxicity in cell culture. The protective activity of D737 was most significant in reducing the toxicity of high molecular weight oligomers of A beta 42. The ability of D737 to prevent A beta 42 aggregation protects against cellular dysfunction and reduces the production/accumulation of reactive oxygen species. Most importantly, treatment with D737 increases the life span and locomotive ability of flies in a Drosophila melanogaster model of Alzheimer disease.
引用
收藏
页码:38992 / 39000
页数:9
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