Proteolytically Stable ααγ-Hybrid Peptides Inhibit the Aggregation and Cytotoxicity of Aβ₄₂

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 Aβ-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aβ₄₂ into fibrils but also disintegrates the aggregated Aβ₄₂ fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aβ₄₂ 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 Aβ₄₂. This is in sharp contrast to the β-sheet conformation of Aβ₄₂ 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 Aβ₄₂ 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.