Decreasing amyloid toxicity through an increased rate of aggregation.

ABSTRACT

Amyloid ß is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the Aß oligomerisation process. While it has been reported that incubation of Amyloid ß (1-42) sequences (Aß42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces toxicity in the neuronal cell line SH-SY5Y. The macrocycle preferentially targets Phe residues in Aß42 complexing them in a 2 1 fashion in neighboring peptide strands. A small but significant structural 'switch' occurs, which induces an increased aggregation rate, suggesting a different cell-uptake mechanism for Aß42 in the presence of CB[8]. Dramatically increasing the rate of Aß42 aggregation with CB[8] bypasses the toxic, oligomeric state offering an alternative approach to counter Alzheimer's disease.