A tetra(ethylene glycol) derivative of benzothiazole aniline enhances Ras-mediated spinogenesis.

Abstract

The tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, is a novel amyloid-binding small molecule that can penetrate the blood-brain barrier and protect cells from Aβ-induced toxicity. However, the effects of Aβ-targeting molecules on other cellular processes, including those that modulate synaptic plasticity, remain unknown. We report here that BTA-EG4 decreases Aβ levels, alters cell surface expression of amyloid precursor protein (APP), and improves memory in wild-type mice. Interestingly, the BTA-EG4-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-EG4 requires APP to regulate dendritic spine density through a Ras signaling-dependent mechanism. Thus, BTA-EG4 may provide broad therapeutic benefits for improving neuronal and cognitive function, and may have implications in neurodegenerative disease therapy.

• Authors: Andrea Megill, Taehee Lee, Amanda Marie DiBattista, Jung Min Song, Matthew H Spitzer, Mark Rubinshtein, Lila K Habib, Christina C Capule, Michael Mayer, R Scott Turner, Alfredo Kirkwood, Jerry Yang, Daniel T S Pak, Hey-Kyoung Lee, Hyang-Sook Hoe
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 33 Issue 22 Pg. 9306-18 (May 29 2013) ISSN: 1529-2401 [Electronic] United States
• PMID: 23719799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• Aniline Compounds
• Benzothiazoles
• Ethylene Glycols
• Receptors, AMPA

Topics

• Amyloid beta-Protein Precursor (genetics)
• Aniline Compounds (pharmacology)
• Animals
• Benzothiazoles (pharmacology)
• Biotinylation
• COS Cells
• Cerebrovascular Circulation (drug effects)
• Chlorocebus aethiops
• Cognition Disorders (chemically induced, psychology)
• Dendritic Spines (drug effects)
• Enzyme-Linked Immunosorbent Assay
• Ethylene Glycols (pharmacology)
• Excitatory Postsynaptic Potentials (drug effects)
• Genes, ras (drug effects)
• Immunohistochemistry
• Long-Term Potentiation (physiology)
• Male
• Maze Learning (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neurogenesis (drug effects)
• Neurons (drug effects)
• Receptors, AMPA (drug effects)