Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect.

Abstract

Fibrillation of amyloid-β peptide (Aβ) is closely associated with the progression of Alzheimer's disease (AD), and so inhibition of Aβ fibrillation has been considered as one of the promising strategies for AD prevention and treatment. Our group has proposed the hydrophobic binding-electrostatic repulsion (HyBER) theory on inhibiting Aβ fibrillation by a surface with mixed negative charges and hydrophobic groups, which provides a new strategy for the design of potent amyloid inhibitors. Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, and its architecture and property vary with the generation number, low-generation dendrimers possessing sparse distributions of terminal groups while high-generation dendrimers having compact surface groups, which offer abundant base materials for further study of the HyBER theory. We have designed a potent amyloid inhibitor with generation 5 PAMAM. To provide new insights into the HyBER mechanism, we have herein proposed to synthesize phenyl-modified PAMAM dendrimers of generations 3 to 6 (G3-P to G6-P) and study the effect of the generation number on Aβ fibrillation. Results show that phenyl derivatives of low-generation dendrimers (G3-P and G4-P) do not show any interference with Aβ aggregation, whereas the phenyl derivatives of high-generation dendrimers (G5-P and G6-P) significantly inhibit Aβ42 aggregation and alter the ultrastructure of Aβ42 aggregates. The results indicate that the density and distribution of surface functional groups on a dendrimer is of great importance for the HyBER effect to happen. The new understanding on the HyBER mechanism would benefit in the development of potent amyloid inhibitors based on the theory.