ABSTRACT
The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aß-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aß42 into fibrils but also disintegrates the aggregated Aß42 fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aß42 at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aß42. This is in sharp contrast to the ß-sheet conformation of Aß42 upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aß42 showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer's disease.
