Role of Metal Nanoparticles as Artificial Chaperones in Modulating the Aggregation Propensity of β-Amyloid (Aβ40) Polypeptide

Abstract

The abnormal cleavage of Amyloid Precursor Protein (APP), and the subsequent aggregation of the cleaved fragments, i.e. beta-Amyloid Polypeptides (Aβ40/42), are linked to the pathogenesis of Alzheimer’s disease (AD)(1). Although molecular chaperones of the proteostasis network look after the fragments and consequent aggregates, they become inefficient with age and stress that result in the accumulation of Aβ40/42 peptides(2,3). Herein, by combining different techniques, we report the impact of metal nanoparticles (MNPs), including Zinc Oxide (ZnO), Cerium Oxide (CeO), and Gold (Au), as artificial Chaperones to modulate the aggregation propensity of Aβ40, the relatively abundant fragment found in the AD patients(4). The binding analysis revealed that the Aβ40 enthalpically binds with ZnONP and CeONP, whereas no binding is observed with AuNP. The binding resulted in flocculation of the complex, trapping Aβ40 monomers into non-amyloid aggregates with the native-like random coil conformation, compared to Aβ40 alone or with AuNP where the peptide adopted fibrillary morphology, which was also confirmed using amyloid-specific thioflavin T fluorescent dye. In conclusion, our results highlight the efficacy of the ZnONP interface in sequestering Aβ40 monomers and preventing their pathological self-assembly, underscoring its potential as a platform to modulate amyloid aggregation.