Abstract
Physiological and pathological ageing (as exemplified by Alzheimer’s disease, AD) are characterized by a progressive decline that also includes cognition. How this decline can be slowed or even reversed is a critical question. Here, we discuss therapeutic ultrasound as a novel modality to achieve this goal. In our studies, we explored three fundamental strategies, (i) scanning ultrasound on its own (SUSonly), (ii) therapeutic ultrasound in concert with intravenously injected microbubbles (which transiently opens the blood–brain barrier, SUS+MB), and (iii) SUS+MB in combination with therapeutic antibodies (SUS+MB+mAb). These studies show SUS+MB effectively clears amyloid and restores memory in amyloid-depositing mice and partially clears Tau and ameliorates memory impairments in Tau transgenic mice, with additional improvements found in combination trials (SUS+MB+mAb). Interestingly, both SUSonly and SUS+MB restored the induction of long-term potentiation (LTP, electrophysiological correlate of memory) in senescent wild-type mice. Both lead to increased neurogenesis, and SUSonly, in particular, resulted in improved spatial memory. We discuss these findings side-by-side with our findings obtained in AD mouse models. We conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may present a treatment option not only for AD but also for enhancing cognition in physiological ageing.
Highlights
What we succeeded to model in the mice was a rather subtle cellular Tau pathology, and since many more advanced models have been generated, both by us and others, yet as we are writing these lines, it is still not fully understood which form of Tau is the major toxic form and, which Tau species needs to be targeted for therapeutic intervention [2,3]
The review will be concluded by discussing the inherent challenges in applying the ultrasound technology to Alzheimer’s disease (AD) and other brain diseases, finishing with a note of encouragement as we believe that there is a vast potential in this technology as it is non-invasive and allows for either localized treatments or global treatments
We explored three fundamental modes of ultrasound application through the skull (Figure 1): (a) SUSonly : application of ultrasound only, which is a pressure wave that travels through the skull into the brain where the modality exerts bioeffects largely via radiation force
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Despite the fact that the first clinical trials using low-intensity ultrasound have already been conducted [6,7], the field is still struggling with ways to apply therapeutic ultrasound effectively and uniformly to the entire brain, and it remains to be shown whether this technology can restore cognition in AD patients. We will briefly mention the principles of therapeutic ultrasound and discuss what renders this technology fundamentally safe This will lead to our preclinical work in wild-type and AD mice as well as larger animal species, hinting at safety and efficacy, as the field moves forward into clinical trials. The review will be concluded by discussing the inherent challenges in applying the ultrasound technology to AD and other brain diseases, finishing with a note of encouragement as we believe that there is a vast potential in this technology as it is non-invasive and allows for either localized treatments (by targeting a small area such as the substantia nigra in Parkinson’s disease) or global treatments (by targeting the entire brain as may be required for AD)
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