Open Accessα-Helix targeting reduces amyloid-β peptide toxicity
Author(s) -
Charlotte Nerelius,
Anna Sandegren,
Hasmik Sargsyan,
R. Raunak,
Hans Leijonmarck,
Urmimala Chatterjee,
André Fisahn,
Sara Imarisio,
David A. Lomas,
Damian C. Crowther,
Roger Strömberg,
Jan Johansson
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0810364106
Subject(s) - neurodegeneration , peptide , toxicity , chemistry , amyloid (mycology) , biochemistry , amyloid beta , biophysics , p3 peptide , helix (gastropod) , oligomer , alzheimer's disease , microbiology and biotechnology , pharmacology , biology , amyloid precursor protein , medicine , disease , inorganic chemistry , ecology , organic chemistry , snail
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 toDrosophila melanogaster expressing human Aβ1–42 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.