A Tetra(Ethylene Glycol) Derivative of Benzothiazole Aniline Enhances Ras-Mediated Spinogenesis
- Andrea Megill1,*,
- Taehee Lee2,*,
- Amanda Marie DiBattista2,
- Jung Min Song2,
- Matthew H. Spitzer2,
- Mark Rubinshtein5,
- Lila K. Habib6,
- Christina C. Capule5,
- Michael Mayer7,
- R. Scott Turner3,
- Alfredo Kirkwood1,
- Jerry Yang5,
- Daniel T. S. Pak4,
- Hey-Kyoung Lee1, and
- Hyang-Sook Hoe2,3,8
- 1Department of Neuroscience, Johns Hopkins University, Baltimore, Maryland 20218,
- 2Departments of Neuroscience,
- 3Neurology, and
- 4Pharmacology, Georgetown University Medical Center, Washington, DC 20057,
- 5Departments of Chemistry and Biochemistry, and
- 6Bioengineering, University of California, San Diego, La Jolla, California 92093,
- 7Departments of Biomedical Engineering and Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, and
- 8Korea Brain Research Institute, Jung-gu, Daegu, Korea 700–010
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Author contributions: A.M., A.M.D., R.S.T., A.K., J.Y., D.T.S.P., H.-K.L., and H.-S.H. designed research; A.M., T.L., A.M.D., J.M.S., M.H.S., M.R., L.K.H., C.C.C., M.M., A.K., J.Y., H.-K.L., and H.-S.H. performed research; R.S.T., A.K., D.T.S.P., H.-K.L., and H.-S.H. contributed unpublished reagents/analytic tools; A.M., T.L., A.M.D., J.M.S., M.H.S., M.R., L.K.H., C.C., M.M., A.K., J.Y., and H.-K.L. analyzed data; A.M., T.L., A.M.D., M.H.S., J.Y., D.T.S.P., H.-K.L., and H.-S.H. wrote the paper.
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↵*A.M. and T.L. contributed equally to this work.
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.
- Received April 2, 2012.
- Revision received April 16, 2013.
- Accepted April 16, 2013.
- Copyright © 2013 the authors 0270-6474/13/339306-13$15.00/0
