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^+MB). We have previously shown that SUS^+MB-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^+MB 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^+MB by treating K369I tau transgenic K3 mice once weekly for 12 weeks. We found that both RNF5 and SUS^+MB treatments on their own significantly reduced tau pathology. In the combination group (RNF5 + SUS^+MB), 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^+MB, RNF5 accumulated heavily within cells across the pyramidal cell layer of the hippocampus, that were negative for MAP2 and p-tau, suggesting that SUS^+MB may not facilitate enhanced RNF5 engagement of intraneuronal tau. Overall, our new findings reveal the complexities of combining tau immunotherapy with SUS^+MB and challenge the view that this is a straight-forward approach.

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