Amyloidogenesis highlighted by designed peptides forming supramolecular self-assemblies

Abstract

Amyloid peptides and proteins are associated with a class of pathologies named amyloidoses such as Alzheimer′s and Parkinson′s diseases. These peptides and proteins, in conditions that are still unclear, fold into a cross-β-sheet structure and form fibrils. To aid the search for therapeutic strategies, detailed knowledge of the mechanisms of fibril formation as well as structural information of toxic intermediates is of current interest. In order to produce a comprehensive model of amyloidogenesis, we have synthesized and characterized designed supramolecular edifices. All edifices fold into cross-β-sheet structure, self-assemble into fibrils and present a neuronal toxicity. The presented results show that fibrillation occurs via the formation of a common key intermediate composed of at least four peptide fragments forming β-strands and stabilized by a hydrogen bonding network and hydrophobic interactions. The cell toxicity study shows that early stage oligomers formed from this minimal structure are related to the toxic species. These edifices are promising tools to decipher in detail the driving forces and factors underlining the aggregation of peptide and proteins into amyloid fibrils.