期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2009
卷号：106
期号：23
页码：9191-9196
DOI：10.1073/pnas.0810364106
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The amyloid-{beta} peptide (A{beta}) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of A{beta} polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger A{beta} assemblies may even increase oligomer-derived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of A{beta} in an {alpha}-helical conformation, inspired by the postulated A{beta} native structure. This is achieved with 2 different classes of compounds that also reduce A{beta} toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human A{beta}1-42 in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central A{beta} {alpha}-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of A{beta} polymerization.
