Prophylactic Active Tau Immunization Leads to Sustained Reduction in Both Tau and Amyloid-β Pathologies in 3xTg Mice

Amyloid-beta (A beta) and tau pathologies are intertwined in Alzheimer's disease, and various immunotherapies targeting these hallmarks are in clinical trials. To determine if tau pathology influences A beta burden and to assess prophylactic benefits, 3xTg and wild-type mice received tau immunization from 2-6 months of age. The mice developed a high IgG titer that was maintained at 22 months of age. Pronounced tau and A beta pathologies were primarily detected in the subiculum/CA1 region, which was therefore the focus of analysis. The therapy reduced histopathological tau aggregates by 70-74% overall (68% in males and 78-86% in females), compared to 3xTg controls. Likewise, western blot analysis revealed a 41% clearance of soluble tau (38-76% in males and 48% in females) and 42-47% clearance of insoluble tau (47-58% in males and 49% in females) in the immunized mice. Furthermore, A beta burden was reduced by 84% overall (61% in males and 97% in females). These benefits were associated with reductions in microgliosis and microhemorrhages. In summary, prophylactic tau immunization not only prevents tau pathology but also A beta deposition and related pathologies in a sustained manner, indicating that tau pathology can promote A beta deposition, and that a short immunization regimen can have a long-lasting beneficial effect.