# Tolcapone Interferes With Key Pathological Features in Alzheimer’s Disease

## TL;DR

Tolcapone, a drug for Parkinson's disease, may help treat Alzheimer's by reducing amyloid-beta toxicity and metal interactions.

## Contribution

The study reveals how tolcapone interacts with amyloid-beta and copper complexes, offering new insights into its neuroprotective mechanisms.

## Key findings

- Tolcapone binds directly to amyloid-beta monomers.
- It acts as a radical scavenger and competes with amyloid-beta for copper ion binding.
- Tolcapone disrupts metal-amyloid-beta complexes, potentially inhibiting toxic aggregation.

## Abstract

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.