Conversion of Aβ42 into a Folded Soluble Native-like Protein using a Semi-random Library of Amphipathic Helices

Abstract

The amyloid cascade model hypothesizes that neurotoxic oligomers or aggregates formed by the Alzheimer amyloid peptide (Aβ) cause disease pathology in Alzheimer's disease. Attempted treatment strategies for Alzheimer's disease have involved either inhibiting Aβ oligomerization or aggregation, or dissolving existing aggregates. Blocking such downhill processes, however, has proved daunting. We have used a different approach that targets Aβ before the oligomerization cascade begins. We predicted that an amphipathic helix could convert Aβ into a native-like protein and inhibit initiation of oligomerization and aggregation. This idea was tested with a designed library and genetic screen. We exhaustively screened a library of semi-randomized amphipathic helical sequences, each expressed as a fusion protein with an Aβ42-yellow fluorescent protein sequence serving as a reporter for folding and solubilization. This yielded an amphipathic helix capable of initiating native-like folding in Aβ42 and preventing aggregation. This amphipathic helix has direct application to Alzheimer's disease therapy development.