Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model

Maria Eleni Karakatsani¹, Tara Kugelman¹, Robin Ji¹, Maria Murillo¹, Shutao Wang¹, Yusuke Niimi¹, Scott A. Small^2,3, Karen E. Duff^2,4,5, Elisa E. Konofagou^1,6✉

1. Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
2. Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA
3. Department of Neurology and Pathology, Columbia University, New York, NY 10032, USA
4. Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA
5. Department of Integrative Neuroscience, Columbia University, New York, NY 10032, USA
6. Department of Radiology, Columbia University, New York, NY 10032, USA

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Citation:
Karakatsani ME, Kugelman T, Ji R, Murillo M, Wang S, Niimi Y, Small SA, Duff KE, Konofagou EE. Unilateral Focused Ultrasound-Induced Blood-Brain Barrier Opening Reduces Phosphorylated Tau from The rTg4510 Mouse Model. Theranostics 2019; 9(18):5396-5411. doi:10.7150/thno.28717. Available from http://www.thno.org/v09p5396.htm

Abstract

The neuropathological hallmarks of Alzheimer's disease include amyloid plaques and neurofibrillary tangles. Tau pathology correlates well with impaired neuronal activity and dementia. Focused ultrasound coupled with systemic administration of microbubbles has previously been shown to open the blood-brain barrier and induce an immune response, which, in an amyloid AD mouse model, resulted in the reduction of the amyloid brain load.

Methods: In this study, we investigated the effect of focused ultrasound at the early stages of tau pathology (pre-tangle) in the rTg4510 mouse model.

Results: Reduction of phosphorylated tau from the hippocampal formation processes, and particularly the pyramidal CA1 neurons, was noted in the ultrasound-treated brains without an associated increase in the phosphorylated tau-affected cell somas, typically associated with disease progression. Attenuation of the pathology was found to correlate well with the ultrasound-initiated immune response without compromising neuronal integrity. Unilateral ultrasound application resulted in a bilateral effect indicating a broader reduction of the phosphorylated tau.

Conclusion: Findings presented herein reinforce the premise of ultrasound in reducing tau pathology and thus curbing the progression of Alzheimer's disease.

Keywords: focused ultrasound, blood-brain barrier opening, tau pathology, Alzheimer's disease