Abstract

A prevalent view in treating age-dependent disorders including Alzheimers disease (AD) is that the underlying amyloid plaque pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound (SUS) treatment at 1 MHz frequency can ameliorate memory deficits in the APP23 mouse model of AD without reducing amyloid-{beta} (A{beta}) burden. Different from previous studies that had shown A{beta} clearance as a consequence of blood-brain barrier (BBB) opening, here, the BBB was not opened as no microbubbles were used. Quantitative proteomics and functional magnetic resonance imaging revealed that ultrasound induced long-lasting functional changes that correlate with the improvement in memory. Intriguingly, the treatment was more effective at a higher frequency (1MHz) than at a frequency within the range currently explored in clinical trials in AD patients (286 kHz). Together, our data suggest frequency-dependent bio-effects of ultrasound and a dissociation of cognitive improvement and A{beta} clearance, with important implications for the design of trials for AD therapies. SummaryThe therapeutic effect of ultrasound on memory in AD mice leads to altered protein expression and improved functional connectivity in the absence of amyloid-{beta} removal. Of two frequencies explored, the higher ultrasound frequency (1 MHz) is more effective.