Unilateral focused-ultrasound-induced blood-brain barrier opening reduces phosphorylated tau in the rTg4510 mouse model Maria Eleni Karakatsani1, Tara Kugelman1, Shutao Wang1, Scott A. Small2,3, Karen Duff2,4,5 and Elisa Konofagou1,6 Columbia University, Biomedical Enginerring, New York, NY Departments of 1Biomedical Engineering, 2Taub Institute for Research on Alzheimer's Disease and the Aging Brain, 3Neurology and Pathology, 4Pathology & Cell Biology, 5Integrative Neuroscience, 6Radiology, Columbia University, New York, NY 10032, USA
Focused ultrasound has been shown to interact with the Alzheimer's disease (AD) pathology and particularly to trigger a mechanism that results in the reduction of the amyloid plaque load. However, a less studied interaction is that of ultrasound with hyperphosphorylated tau protein. At the early stages of Alzheimer's disease, the tau protein is primarily localized in the axons while in late pathology, somatodendritic tau becomes more pronounced. Here, we investigate the interaction of focused ultrasound-induced blood-brain barrier opening with the tau distribution. For this study the initial cohort included ten 3.5-month-old rTg4510 mice, 5 of which received a hippocampal sonication (MI=0.36) once per week for 4 consecutive weeks, and five 5.6-month-old rTg4510 mice. The day after the last sonication, the mice were sacrificed and their brains counter-stained for tau protein (AT8) and microglia activation (CD68). A custom algorithm was constructed to quantify the number of cells by employing the Hough transformation. The axonal distribution of the tau-marker and the CD68 density were assessed through intensity-based quantification. Monte Carlo was employed to increase the robustness of the algorithm in estimating the axonal length affected by the pathological protein. Analysis of the spatial distribution of phosphorylated tau protein in the brains treated with ultrasound showed a marked reduction of the pathological marker from the processes that reside in the hippocampal formation and particularly the pyramidal CA1 neurons without an associated increase in the soma. Attenuation of tau pathology correlated with increased microglial activity (r2=0.3285;β=-2.136; P<0.0001). Unilateral application of ultrasound resulted in a bilateral effect indicating that ultrasound might broadly reduce phosphorylated tau through a single targeted sonication.These findings indicate that focused ultrasound may be a rate-limiting factor of the hyperphosphorylated tau progression at the early AD stages.
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