Harnessing the immune system to target pathological tau protein has recently become an attractive therapeutic approach for frontotemporal dementia and related tauopathies. We previously reported on the feasibility of active immunization targeting pathological tau in a mouse model of frontotemporal dementia. The promise of tau immunotherapy has now been confirmed by other groups. In active immunizations, a protein or peptide is administered with an immunostimulatory compound (adjuvant) to elicit an immune response against the protein/peptide. For clearance of protein aggregates in neurodegenerative diseases, an antibody response is generally considered beneficial whereas activation of killer T cells is detrimental. While the active approach is very promising, and can be tailored to primarily induce an antibody response, it is inherently associated with a slight risk of autoimmune side effects, such as killer T cell activation. These potential adverse reactions may be avoided with direct administration of antibodies that are designed to clear pathological tau. Hence, the Specific Aim of the proposal is to assess the therapeutic utility of monoclonal tau antibodies in a mouse model of frontotemporal dementia. This passive approach is more likely to be fast-tracked for clinical trials, compared to active immunizations. Overall, this proposal may lead to a novel therapy for frontotemporal dementia that can be tested in humans in the near future.