Screening π-Extended Ruthenium(II) Complexes for the Photoinduced Oxidative Modulation of Amyloid-β Peptide Aggregation

Controlling the aggregation of amyloid-β (Aβ) peptides offers a promising strategy to mitigate Alzheimer's disease (AD). Herein, we introduce a series of photoactivatable Ru(II) complexes (<b>Ru1-8</b>) designed to efficiently generate singlet oxygen (¹O₂) and subsequently oxidatively modify the Aβ peptide. Upon light activation, these complexes rapidly direct Aβ_1-42 aggregation toward high molecular weight amorphous species, with <b>Ru1</b> demonstrating the most pronounced effect. Transmission electron microscopy (TEM) revealed that the amorphous aggregates formed immediately and persist over time. Complementary assays, including bicinchoninic acid (BCA) quantification and Western blotting, demonstrated rapid photoinduced aggregation and a decrease of soluble peptide upon photoactivation, while proteinase-K digestion showed that the resulting amorphous species are more susceptible to proteolysis in comparison to canonical fibrils. Control experiments under anaerobic conditions and in the presence of an ¹O₂ scavenger suggest that these effects are oxygen-dependent. Notably, photoactivation of <b>Ru1</b> in the presence of preformed fibrils results in a morphology change to degradable amorphous aggregates, providing both preventive and disruptive activity. Together, these findings establish photoactivatable <b>Ru1</b> as a light-controlled chemical tool capable of redirecting Aβ aggregation, enhancing aggregate protease degradation, and offering a versatile platform for therapeutic exploration.