A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis

Abstract

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG(4), is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from A beta-induced toxicity. However, the effects of A beta-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG(4) decreases A beta levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG(4)-mediated behavioral improvement is not correlated with LTP, but with increased spinogenesis. The higher dendritic spine density reflects an increase in the number of functional synapses as determined by increased miniature EPSC (mEPSC) frequency without changes in presynaptic parameters or postsynaptic mEPSC amplitude. Additionally, BTA-EG(4) requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG(4) may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.