[alpha]-Helix targeting reduces amyloid-[beta] peptide toxicity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 23; p. 9191
• Main Authors: Nerelius, C, Sandegren, A, Sargsyan, H, Raunak, R, Leijonmarck, H, Chatterjee, U, Fisahn, A, Imarisio, S, Lomas, D A, Crowther, D C, Strömberg, R, Johansson, J
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 09.06.2009
• Subjects: Alzheimer's disease; Cell culture; Insects; Molecular structure; Molecules; Peptides; Toxicity
• ISSN: 0027-8424; 1091-6490

The amyloid-β peptide (Aβ) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of Aβ polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger Aβ 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 Aβ in an α-helical conformation, inspired by the postulated Aβ native structure. This is achieved with 2 different classes of compounds that also reduce Aβ 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 Aβ... in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central Aβ α-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of Aβ polymerization. (ProQuest: ... denotes formulae/symbols omitted.)