Light-triggered dissociation of self-assembled β-amyloid aggregates into small, nontoxic fragments by ruthenium (II) complex

Abstract

The self-assembly of β-amyloid (Aβ) peptides into highly stable plaques is a major hallmark of Alzheimer's disease. Here, we report visible light-driven dissociation of β-sheet-rich Aβ aggregates into small, nontoxic fragments using ruthenium (II) complex {[Ru(bpy)₃]²⁺} that functions as a highly sensitive, biocompatible, photoresponsive anti-Aβ agent. According to our multiple analyses using thioflavin T, bicinchoninic acid, dynamic light scattering, atomic force microscopy, circular dichroism, and Fourier transform infrared spectroscopy, [Ru(bpy)₃]²⁺ successfully disassembled Aβ aggregates by destabilizing the β-sheet secondary structure under illumination of white light-emitting diode light. We validated that photoexcited [Ru(bpy)₃]²⁺ causes oxidative damages of Aβ peptides, resulting in the dissociation of Aβ aggregates. The efficacy of [Ru(bpy)₃]²⁺ is attributed to reactive oxygen species, such as singlet oxygen, generated from [Ru(bpy)₃]²⁺ that absorbed photon energy in the visible range. Furthermore, photoexcited [Ru(bpy)₃]²⁺ strongly inhibited the self-assembly of Aβ monomers even at concentrations as low as 1 nM and reduced the cytotoxicity of Aβ aggregates.

Statement of significance: Alzheimer's disease is the most common progressive neurodegenerative disease, affecting more than 13% of the population over age 65. Over the last decades, researchers have focused on understanding the mechanism of amyloid formation, the hallmark of various amyloid diseases including Alzheimer's and Parkinson's. In this paper, we successfully demonstrate the dissociation of β-Amyloid (Aβ) aggregates into small, less-amyloidic fragments by photoexcited [Ru(bpy)₃]²⁺ through destabilization of β-sheet secondary structure. We validated the light-triggered dissociation of amyloid structure using multiple analytical tools. Furthermore, we confirmed that photoexcited [Ru(bpy)₃]²⁺ reduces cytotoxicity of Aβ aggregates. Our work should open a new horizon in the study of Alzheimer's amyloid aggregation by showing the potential of photoexcited dye molecules as an alternative therapeutic strategy for treating Alzheimer's disease in future.

Keywords: Alzheimer's disease; Dissociation; Peptide self-assembly; Photo-oxidation; Ruthenium (II) complex; β-Amyloid.