Poly(4-styrenesulfonate) as an Inhibitor of A/?40 Amyloid Fibril Formation

摘要

The formation of amyloid, a cross-β-sheet fibrillar aggregate of proteins, is associated with a variety of neurodegenerative diseases. Amyloidogenic proteins such as β-amyloid (Aβ) are known to exist with a large amount of polyelectrolyte macromolecules in vivo. The exact nature of Aβ-polyelectrolyte interactions and their roles in Aβ-aggregation are largely unknown. In this regard, we report the inhibiting effect of an anionic polyelectrolyte poly(4-styrenesulfonate) (PSS) on the aggregation of Aβ40 peptide. The results demonstrate the strong inhibition potential of PSS on the aggregation of A/HO and imply the dominant role of hydrophobicity of the polyelectrolyte in reducing the propensity of Aβ40 amyloid formation. Additional studies with poly(vinyl sulfate) (PVS) and p-toluenesulfonate (PTS), which share similar charge density with PSS except the former lacking the nonpolar aromatic side chain and the latter the aliphatic hydrocarbon backbone, reveal that the presence of both aliphatic backbone and aromatic side chain group in PSS is essential for its Aβ-aggregation inhibition activity. The interactions involved in the Aβ40—PSS complex were further investigated using molecular dynamics (MD) simulation. Our results provide new insights into the structural interplay between polyelectrolytes and Aβ peptide, facilitating the ultimate understanding of amyloid formation in Alzheimer's disease. The results should assist in developing novel polyelectrolytes as potential chemical tools to study amyloid aggregation.