Attenuating the Toxicity of Amyloid-Beta Aggregation with Specific Species

Abstract

The deposition into amyloid plaques of the amyloid-β peptide (Aβ) is a hallmark of Alzheimer's disease (AD). Increasing evidence suggests that soluble Aβ oligomers are the pathological species primarily responsible for AD onset and progression. Shifting the aggregation pathway towards the formation of non-toxic aggregated species by specific compounds could thus prove an effective therapeutic strategy for AD. Herein, we employ an array of biophysical techniques, including fluorescence-based chemical kinetics, Atomic Force Microscopy, Nuclear Magnetic Resonance, and absorbance spectroscopy, and in vivo techniques, including cells and C. elegans, to characterise compounds for their ability to mitigate the aggregation of Aβ. We find structurally similar compounds that 1) regulate protein assembly by modulating the microscopic processes governing aggregation, 2) interact with primary species resulting in increased fibrilization in vitro and in vivo, 3) drive the formation of shorter, more mature fibrils, 4) generate larger, less hydrophobic, and less toxic aggregates from oligomers after incubation with pre-formed oligomers, and 5) in the case of one species, eliminates Aβ42-induced toxicity in a worm model of AD. These findings suggest reducing the toxicity associated with Aβ42 aggregation could be explored to find viable therapeutic strategies for the treatment of AD.