Tolcapone Derivative (Tol-D) Inhibits Aβ42 Fibrillogenesis and Ameliorates Aβ42-Induced Cytotoxicity and Cognitive...

Abnormal aggregation and subsequent fibrillogenesis of amyloid-β protein (Aβ) can cause Alzheimer's disease (AD). Thus, the discovery of effective drugs that inhibit Aβ fibrillogenesis in the brain is important for the treatment of AD. Our previous study has proven that tolcapone inhibits Aβ fibrillogenesis and alleviates its cytotoxicity based on systematic in vitro and in vivo experiments. However, the severe hepatotoxicity of tolcapone seriously limits its further potential application in the treatment of AD. Herein, an inhibitory effect of a low-toxicity tolcapone derivative (Tol-D) on Aβ fibrillogenesis was explored. Based on the thioflavin T fluorescence data, Tol-D inhibited Aβ fibrillogenesis, and the inhibitory capacity increased with the increase of its concentrations with an IC₅₀ of ∼8.99 μM. The results of cytotoxicity showed that Tol-D greatly reduced the cytotoxicity induced by Aβ42 fibrillogenesis. Moreover, Tol-D significantly alleviated Aβ deposits and extended the lifespan of nematodes in transgenic Caenorhabditis elegans models. Finally, Tol-D significantly relieved Aβ-induced cognitive dysfunction in mice experiments. Overall, the above experimental results indicated that Tol-D is a novel candidate therapeutic compound for the treatment of AD.