The cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy

Background Using a variety of cell and animal model systems we demonstrate that the cytosolic antibody receptor and E3 ligase TRIM21 plays a critical role in antibody‐mediated protection against tau pathology Method Experiments with organotypic hippocampal slice cultures and in vivo studies in mouse models were conducted to study the role of TRIM21 in tau immunotherapy. Result We demonstrate that tau:antibody complexes were internalised to the cytosol of neurons, enabling TRIM21 engagement and thereby protecting against seeded aggregation. Crucially, antibody‐mediated protection against tau pathology was lost in mice lacking TRIM21 Conclusion The cytosolic compartment provides a site of immunotherapeutic protection, which can help in the design of antibody‐based therapies in neurodegenerative disease.