Nootropic benzothiazoles promote dendritic spine formation by targeting fascin-1

Abstract

Identifying new drug targets to enhance memory and learning is essential for treating neurodegenerative diseases, such as Alzheimer's disease. We previously showed that benzothiazole amphiphiles can improve memory and learning by increasing dendritic spine and synaptic density in both WT mice and in a transgenic Alzheimer's model mice. The cellular target for this class of compounds, however, was unknown. Using a photoaffinity-labeling approach, we identify fascin-1 as the major protein target in neurons for these compounds. These compounds enhance spine density by directly modulating actin dynamics, increasing the capability of fascin-1 to bundle actin filaments. Molecular docking and structure-guided mutagenesis studies reveal a distinct binding site on fascin-1, differing in both location and function from previously reported fascin-1-targeting molecules, opening exciting new avenues for selectively tuning fascin-1 activity in the brain.

Keywords: Alzheimer’s disease; actin; benzothiazoles; dendritic spine; fascin; molecular docking; mutagenesis; neuron.