Understanding Early Amyloid-ß Aggregation to Engineer Polyacid-Functionalized Nanoparticles as an Inhibitor Design Platform

Alzheimer’s disease (AD) is characterized by the presence of amyloid-ß (Aß) protein aggregates in the brains of those afflicted. This protein aggregates via a complex pathway to progress from monomers to soluble oligomers and ultimately insoluble fibrils. Due to the dynamic nature of aggregation, it has proven exceedingly difficult to determine the precise interactions that lead to the formation of transient oligomers. A statistical thermodynamic model has been developed to elucidate these interactions. Aß was simulated using fully-atomistic replica exchange molecular dynamics. We use an ensemble of 5 × 105 configurations taken from these simulations as input for a self-consistent field theory (SCFT) that explicitly accounts for the size, shape and charge distribution of the amino acids comprising Aß as well as all molecular species present in solution. The solution of the model equations provides a prediction of the probabilities of the configurations of the interacting Aß monomers and the potential of mean force between two monomers during the dimerization process. This model constitutes a powerful methodology to elucidate the underlying physics of the Aß dimerization process as a function of pH, temperature and salt concentration. Gold nanoparticles (NPs) are a promising class of materials for medical applications due to the unique properties that particles in this size range have on biological systems. Moreover, these NPs can be functionalized with ligands to effect a veritable cornucopia of biological responses. We have performed a central composite design of experiment to determine the effects of NP size and the length of end-grafted polyacrylic acid (PAA) molecules on the aggregation of Aß We find that a complex interplay exists between these two physical properties with respect to Aß interactions that is dependent on the bulk ion concentration. In particular, a regression analysis of the measured data indicates that NP diameter is negatively correlated with Aß aggregation lag time and that an optimum length of PAA exists at low ion concentrations with respect to this response. We develop another SCFT to model the behavior of the PAA on the NPs’ surface. We present this theory with two distinct formulations each employing a different polymer model and discuss the implications and practicality of their respective use. These theories allow us to make predictions regarding the effects that the polymers have on local solution conditions as a function of the same bulk solution conditions that modulate Aß aggregation and to put our experimental observations in a more general theoretical context. The capacity to synthesize, characterize and test the efficacy of PAA-functionalized NPs as Aß aggregation inhibitors coupled with accurate theoretical modeling of the thermodynamics and molecular organization of the system at the nanoscale constitutes a robust platform with which to design AD therapeutics