Aβ aggregation inhibition via peptide-conjugated gold nanoclusters: Mechanistic insights and therapeutic potential

Abstract

To slow the progression of Alzheimer’s disease (AD), eliminating amyloid β (Aβ) or inhibiting its abnormal aggregation has emerged as a promising strategy. Among the molecules developed to inhibit Aβ aggregation, gold nanoclusters (AuNCs) stand out due to their excellent biocompatibility and high efficiency in modulating Aβ aggregation. However, the currently reported AuNCs often lack specificity toward Aβ, which may limit their in vivo applications. In this study, we synthesized a novel gold nanocluster (AuCRHA1) functionalized with the peptide CRHRHKLVFF to achieve specific recognition of Aβ. Our results demonstrated that AuCRHA1 effectively inhibited Aβ aggregation and reduced its cytotoxicity in complex solutions, underscoring the robustness of our design. By combining isothermal titration calorimetry results with mathematical modeling, molecular docking, and molecular dynamics simulation, we identified two main inhibitory roles of AuCRHA1: binding to free Aβ monomers to reduce the effective Aβ concentration and depolymerizing mature fibrils. Moreover, treatment with AuCRHA1 significantly extended the lifespan of Caenorhabditis elegans, an AD model organism. Collectively, this work highlights the potential of AuCRHA1 as a promising agent for inhibiting Aβ aggregation and its application in preventing or treating AD.

Keywords

• Amyloid β
• Gold nanocluster
• Peptide
• Inhibitor
• Alzheimer’s disease