Targeting Hyperphosphorylated Tau Protein with a Monoclonal Antibody at an Advanced Stage of Tau Pathology Improves Cognition in a Mouse Model

Immunotherapy targeting pathological tau is emerging as a promising approach to treat tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia. We have previously shown that prophylactic active or passive tau immunotherapy, starting at 2-3 months of age, clears tau pathology and improves function (Asuni A. et al., J. Neurosci. 2007, Boutajangout A. et al., J. Neurosci. 2010, Boutajangout A. et al., ICAD 2010). Here we assessed if a phospho-specific monoclonal, 4E6G7, targeting the same epitope, would be efficacious if treatment commenced at an advanced stage of tau pathology (8-9 months). htau/PS1 mice without mouse tau protein (8-9 months) were injected intraperitoneally (250 μg/125 μl) once per week with a novel phospho-specific tau monoclonal, 4E6G7 (n = 9) or pooled mouse IgG (n = 10) for a total of 13 injections. Their behavior was analyzed at 11-12 months of age and brain tissue subsequently harvested for analyses of treatment efficacy. The immunized mice (n = 7-8) performed substantially better than controls (n = 6) on the Radial Arm Maze (p < 0.0001; post hoc, p < 0.01-0.001 on days 2, 3, 5-9), the Closed Field Symmetrical Maze with 35-69% fewer errors in simple, intermediate and complex tasks (p < 0.05-0.003), and the Object Recognition Task (63% time spent with a novel object vs. 46% for controls, p < 0.05). The groups did not differ in various sensorimotor tasks, indicating that the robust cognitive improvements cannot be explained by sensorimotor effects, which further strengthens our results. Interestingly, more controls died during the study (40%) than immunized mice (22%), providing an additional support for the beneficial effect of the monoclonal tau antibody. Histological and biochemical analyses are underway. These results indicate pronounced efficacy of passive tau immunotherapy at an advanced stage of tauopathy, which suggests that this approach may be beneficial after clinical onset of AD and other tauopathies.