Oligomeric tau-targeted immunotherapy in Tg4510 mice

Sulana Schroeder, Aurelie Joly-Amado, Ahlam Soliman, Urmi Sengupta, Rakiz Kayed, Marcia N. Gordon, David Morgan

Finding ways to reverse or prevent the consequences of pathogenic tau in the brain is of considerable importance for treatment of Alzheimer's disease and other tauopathies. Immunotherapy against tau has shown promise in several mouse models. In particular, an antibody with selectivity for oligomeric forms of tau, tau oligomer monoclonal antibody (TOMA), has shown rescue of the behavioral phenotype in several murine models of tau deposition. In this study, we examined the capacity of TOMA to rescue the behavioral, histological, and neurochemical consequences of tau deposition in the aggressive Tg4510 model. We treated mice biweekly with 60 μg TOMA i.p. from 3.5 to 8 months of age. Near the end of the treatment, we found that oligomeric tau was elevated in both the CSF and in plasma. Further, we could detect mouse IgG in Tg4510 mouse brain after TOMA treatment, but not after injection with mouse IgG1 as control. However, we did not find significant reductions in behavioral deficits or tau deposits by either histological or biochemical measurements. These data suggest that there is some exposure of the Tg4510 mouse brain to TOMA, but it was inadequate to affect the phenotype in these mice at the doses used. These data are consistent with other observations that the rapidly depositing Tg4510 mouse is a challenging model in which to demonstrate efficacy of tau-lowering treatments compared to some other preclinical models of tau deposition/overexpression.