α-Helix Targeting Reduces Amyloid-ß Peptide Toxicity

The amyloid-ß peptide (Aß) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of Aß polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger Aß assemblies may even increase oligomerderived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of Aß in an a-helical conformation, inspired by the postulated Aß native structure. This is achieved with 2 different classes of compounds that also reduce Aß 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 Aß₁₋₄₂ in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central Aß α-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of Aß polymerization.