Synthesis and mechanistic study of Aβ42 C-terminus domain derived tetrapeptides that inhibit Alzheimer’s Aβ-aggregation-induced neurotoxicity

Amyloid plaque formation in the brain is mainly responsible for the onset of Alzheimer’s disease (AD). Structure-based peptides have gained importance in recent years, and rational design of the peptide sequences for the prevention of Aβ-aggregation and related toxicity is imperative. In this study, we investigate the structural modification of tetrapeptides derived from the hydrophobic C-terminal region of Aβ₄₂ “VVIA-NH₂” and its retro-sequence “AIVV-NH₂.” A preliminary screening of synthesized peptides through an MTT cell viability assay followed by a ThT fluorescence assay revealed a peptide 13 (Ala-Ile-Aib-Val-NH₂) that showed protection against Aβ-aggregation and associated neurotoxicity. The presence of the α-helix inducer “Aib” in peptide 13 manifested the conformational transition from cross-β-sheets to α-helical content in Aβ₄₂. The absence of fibrils in electron microscopic analysis suggested the inhibitory potential of peptide 13. The HRMS, DLS, and ANS studies further confirmed the inhibitory activity of 13, and no cytotoxicity was observed. The structure-based peptide described herein is a promising amyloid-β inhibitor and provides a new lead for the development of AD therapeutics.