Ultrasound-mediated delivery of novel tau-specific monoclonal antibody enhances brain uptake but not therapeutic efficacy.

Tau-specific immunotherapy is an attractive strategy for the treatment of Alzheimer's disease and other tauopathies. However, effectively targeting tau in the brain remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes an estimated >99% of peripherally administered antibodies. However, their transport across the BBB can be facilitated by a novel modality, low-intensity scanning ultrasound used in combination with intravenously injected microbubbles (SUS). We have previously shown that SUS-mediated delivery of a tau-specific antibody in a single-chain (scFv) format to tau transgenic mice enhanced brain and neuronal uptake and subsequently, reduced tau pathology and improved behavioural outcomes to a larger extent than either scFv or SUS on its own. Here we generated a novel tau-specific monoclonal antibody, RNF5, and validated it in its IgG format in the presence or absence of SUS by treating K369I tau transgenic K3 mice once weekly for 12 weeks. We found that both RNF5 and SUS treatments on their own significantly reduced tau pathology. In the combination group (RNF5 + SUS), however, despite increased antibody localization in the brain, there were no further reductions in tau pathology when compared to RNF5 treatment alone. Furthermore, following SUS, RNF5 accumulated heavily within cells across the pyramidal cell layer of the hippocampus, that were negative for MAP2 and p-tau, suggesting that SUS may not facilitate enhanced RNF5 engagement of intraneuronal tau. Overall, our new findings reveal the complexities of combining tau immunotherapy with SUS and challenge the view that this is a straight-forward approach.