Passive tau immunotherapy diminishes functional decline and clears tau aggregates in a mouse model of tauopathy

Abstract

Targeting hyperphosphorylated tau by immunotherapy is emerging as a promising approach to treat tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia. We have previously reported that active tau immunization clears tau aggregates from the brain and attenuates or prevents functional impairments in two different tangle model mice. Here we assessed the efficacy of passive immunization with the PHF1 antibody, which targets a phospho-epitope within one of our active immunogens. Homozygous JNPL3 P301L mice (2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG (250 μg/125 μl; n = 10 per group) for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue subsequently harvested for analysis of treatment efficacy. The treated mice performed better than controls on the traverse beam task (p < 0.03), and had 58% less tau pathology in the dentate gyrus of the hippocampus (p = 0.02). Plasma levels of PHF1 correlated inversely with tau pathology in the brain stem (p < 0.01) and motor cortex (p = 0.06), indicating that higher dose of antibodies may have a greater therapeutic effect. As assessed by Western blots, the antibody therapy reduced the ratio of pathological- to total tau (PHF1/B19) by 27% (p < 0.0001) but levels of soluble tau were unchanged, compared to controls. Further analysis is underway with other tau antibodies and markers of associated pathologies. These results indicate that passive immunization with tau antibodies can decrease tau pathology and functional impairments in the JNPL3 P301L model. Future studies will determine the feasibility of this approach with other monoclonals and in different tangle models that more closely resemble AD.