Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions

Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.

Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments.

Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes. Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.