OO024 - ULTRASOUND-MEDIATED DELIVERY OF A NOVEL ANTI-TAU ANTIBODY INCREASES BRAIN AND NEURONAL UPTAKE BUT DOES NOT ENHANCE THERAPEUTIC EFFICACY IN K369I TAU TRANSGENIC MICE (ID 383)
Abstract
Aims
Tau-specific immunotherapy is an attractive therapeutic strategy for the treatment of Alzheimer’s disease and other tauopathies. However, targeting tau effectively remains a considerable challenge due to the restrictive nature of the blood-brain barrier (BBB), which excludes 99.9% of peripherally administered antibodies. Furthermore, tau is predominantly localised within neurons. We have previously shown that intravenous injection of microbubbles followed by the application of scanning ultrasound (SUS+MB) can transiently open the BBB, allowing up to 19-fold increased IgG antibody uptake by the brain. However, therapeutic efficacy after enhanced brain delivery has not been explored.
Methods
To assess whether ultrasound-mediated delivery of tau-specific IgGs enhances therapeutic efficacy, K369I tau transgenic mice were passively immunised once weekly for 12 weeks with a novel pan-tau antibody, RNF5, in combination with SUS+MB, followed by histological and biochemical analysis.
Results
Treatment with either RNF5 or SUS+MB alone reduced hyperphosphorylated tau. However, the combination treatment (RNF5+SUS+MB), while effective, had no additive effects on tau reduction, despite increased delivery to the brain. This was due to acute neuronal degeneration and inflammation in the areas where RNF5 had extravasated into the brain parenchyma and been internalised into neurons.
Conclusions
Overall, our findings suggest that higher concentrations of IgG in the brain may be detrimental and that the benefit of SUS+MB might reach a threshold such that increased antibody concentration in the brain may become toxic. What renders brain tissue susceptible is currently being investigated. Together, more research is warranted to exploit SUS+MB as a delivery modality.
