Poly(4-styrenesulfonate)
as an Inhibitor of Aβ40
Amyloid Fibril Formation
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Abstract
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 Aβ40 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 <i>p</i>-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