Rational Design of Surface Modified Nanoparticles for Modulation of Amyloid Beta Aggregation

Abstract

Alzheimer's disease (AD) is a debilitating disease that is the sixth leading cause of death in the United States. It is the only disease that is in the top ten most lethal that currently has no known cure. One of the hallmarks of AD is the presence of amyloid-β (Aβ) aggregates in the brains of those afflicted. Current understanding of the etiology of AD points to general disruption of the aggregation pathway as a promising strategy for a potential cure.Surface modified nanoparticles have demonstrated striking effectiveness as inhibitors of Aβ aggregation. We have observed inhibition of Aβ aggregation by polyacrylic acid-coated gold nanospheres at substoichiometric ratios as low as 1:2,000,000. Nanoparticles coated with weak polyelectrolytes can produce significant local effects on pH of which Aβ aggregation is highly dependent. It is through this mechanism that we propose that these nanospheres can inhibit with such potency. A molecular theory has been developed in which intramolecular interactions are treated exactly and intermolecular interactions are treated within a mean-field approximation. The theory also accounts for the effects of curvature in the system present on the molecular scale with very good agreement with experimental data.When tethered to a surface, weak polyelectrolytes confine electric charge. To mitigate the resulting energetically unfavorable electrostatic repulsions, the polymer layer of polyacrylic-acid coated nanospheres will recruit hydronium ions in weakly ionic aqueous solutions, locally lowering the pH. When the same conditions are used to parameterize the theoretical model as were used in experiment, the resulting sphere of lowered pH is pervasive enough to cause the observed abrogation of Aβ aggregation. Together, surface modified nanoparticles with this robust and accurate molecular model represent a powerful platform to engineer nanotechologies to modulate Aβ aggregation.