Destroying Toxic Amyloid-beta Aggregation with Photoactive Transition Metal Complexes

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterized by memory loss, motor skill loss, and eventually death that currently affects at least 5.8 million Americans.¹ This number is projected to more than double in the next 30 years.¹ Much effort has gone into determining the exact cause of onset of AD as well as developing strategies to mitigate its symptoms, however, there are currently are no substantial methods of prevention, slowing, or cure.¹ For nearly 30 years, the prevailing hypothesis for AD centers around the formation of neurotoxic amyloid-beta peptides (A-beta).² In the AD brain, A-beta peptides accumulate into a spectrum of larger aggregates, each type of which have unique toxic properties and cause a cascade of other pathologies consistent with AD. Modifying these peptides along their aggregation pathway or inhibiting their aggregation altogether is crucial for controlling the toxicity they trigger. One method of modification is oxidative destruction of A-beta that is performed by reactive oxygen species (ROS) such as singlet oxygen (¹O₂). Singlet oxygen can be produced relatively simply by irradiating a photoactive compound in the presence of oxygen.³ Clinically, this strategy of photodynamic therapy has been approved and is now employed for mitochondria-targeted cancer treatment.⁴ Photoactive complexes that incorporate late transition metals are especially quantum-efficient (e.g., [Ru(bpy)₃]²⁺) and have demonstrated substantial ability to generate ¹O₂.⁵ In this talk, three late transition metal photoactive complexes, including [Ru(bpy)₃]²⁺ and two Ir(III)-phenylquinoline complexes are studied for their photophysical properties and effects on the aggregation of A-beta at physiological conditions.^5-7 These complexes highlight a balance between efficient photophysical properties and peptide interaction as they demonstrate varying abilities to destroy A-beta aggregates, alter A-beta aggregation, and steeply enhance neuronal cell viability up to 95% in one study.

References:

¹ Alzheimer’s Association. 2018 Alzheimer’s Disease Facts and Figures. Alzheimer's Dementia 2018, 13, 325.

² Hardy, J. A.; Higgins, G. A., Science. 1992, 256, 184.

³ Lim, M. H. and coworkers, Inorg. Chem. 2018, 58, 8.

⁴ American Cancer Society. Getting Photodynamic Therapy. 2019.

https://www.cancer.org/treatment/treatments-and-side-effects/treatmenttypes/radiation/photodynamic-therapy.html.

⁵ Park, C. B. and coworkers, Acta Biomat. 2018, 67, 147.

⁶ Lim, M. H. and coworkers, Chem.-Eur. J. 2017, 23, 1645.

⁷ Lim, M. H. and coworkers, Chem. Sci. 2019, 10, 6855