Tolcapone Interferes With Key Pathological Features in Alzheimer’s Disease

Tolcapone, a clinically approved drug for the treatment of Parkinson's disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid-β aggregation and toxicity, which are hallmark features of Alzheimer's disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age-related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid-β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal-amyloid-β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper-free amyloid-β and copper-associated amyloid-β complexes, using a combination of techniques including UV-vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid-β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid-β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal-free and metal aggregation pathways by preventing metal coordination to amyloid-β or disrupting preformed amyloid-β-metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.