α-Helix targeting reduces amyloid-β peptide toxicity

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 beta-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.