One of the greatest challenges for the treatment of neurodegenerative disease is crossing the blood-brain barrier. Nisbet et al. demonstrate that non-invasive scanning ultrasound increases the delivery of tau-specific single-chain antibody fragments across the blood-brain barrier and into neurons of tau transgenic mice, reducing anxiety-like behaviour and tau pathology.

Tau is a scaffolding protein that serves multiple cellular functions that are perturbed in neurodegenerative diseases, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We have recently shown that amyloid‐β, the second hallmark of AD, induces de novo protein synthesis of tau. Importantly, this activation was found to be tau‐dependent, raising the question of whether FTD‐tau by itself affects protein synthesis. We therefore applied non‐canonical amino acid labelling to visualise and identify newly synthesised proteins in the K369I tau transgenic K3 mouse model of FTD. This revealed massively decreased protein synthesis in neurons containing pathologically phosphorylated tau, a finding confirmed in P301L mutant tau transgenic rTg4510 mice. Using quantitative SWATH‐MS proteomics, we identified changes in 247 proteins of the de novo proteome of K3 mice. These included decreased synthesis of the ribosomal proteins RPL23, RPLP0, RPL19 and RPS16, a finding that was validated in both K3 and rTg4510 mice. Together, our findings present a potential pathomechanism by which pathological tau interferes with cellular functions through the dysregulation of ribosomal protein synthesis.

Advanced physiological aging is associated with impaired cognitive performance and the inability to induce long-term potentiation (LTP), an electrophysiological correlate of memory. Here, we demonstrate in the physiologically aged, senescent mouse brain that scanning ultrasound combined with microbubbles (SUS+MB), by transiently opening the blood–brain barrier, fully restores LTP induction in the dentate gyrus of the hippocampus. Intriguingly, SUS treatment without microbubbles (SUSonly), i.e., without the uptake of blood-borne factors, proved even more effective, not only restoring LTP, but also ameliorating the spatial learning deficits of the aged mice. This functional improvement is accompanied by an altered milieu of the aged hippocampus, including a lower density of perineuronal nets, increased neurogenesis, and synaptic signaling, which collectively results in improved spatial learning. We therefore conclude that therapeutic ultrasound is a non-invasive, pleiotropic modality that may enhance cognition in elderly humans.