IMMUNOTHERAPY-TARGETING TAU BLOCKS TAU PATHOLOGY INDUCED BY ALZHEIMER’S HYPERPHOSPHORYLATED TAU IN TRIPLE-TRANSGENIC AD MICE

Abstract

Accumulating evidence indicates that tau pathology can spread from neuron to neuron by intake and coaggregation of the hyperphosphorylated tau seeds with the host neuron protein. Therefore, removal of tau seeds by immunization with tau antibodies could provide a potential therapeutic opportunity to block the spread of tau pathology in Alzheimer's disease (AD) and other tauopathies. Female, 11-12-month old 3×Tg-AD mice were intravenously immunized weekly with 15 μg/injection of mouse monoclonal antibody 43D targeting tau 6-18, or as control with mouse IgG for 6 weeks. AD P-tau isolated from a frozen autopsied AD brain was unilaterally injected into right hippocampus on the day of the second dose of immunization. Tau pathology was assessed by immunohistochemical staining. Injection of AD P-tau into the hippocampus of 11-12-month old of 3×Tg-AD mouse induced tau aggregation as early as six weeks in the hippocampus after AD P-tau injection, and promotes the spread of tau pathology to the contralateral hippocampus. Tau pathology was thioflavin-S negative even in naïve 18-month-old 3×Tg-AD mice. However, tau pathology templated by AD P-tau exhibited thioflavin-S positive and was about 2-fold more in 13.5-month-old 3×Tg-AD mice than that seen in naïve 18-month-old 3×Tg-AD mice. Immunization with tau antibody 43D against tau 6-18 dramatically blocked AD P-tau seeding in the ipsilateral hippocampus and inhibited its propagation to the contralateral side in 3×Tg-AD mice. These studies indicate (1) that AD P-tau injected 3×Tg-AD mice represent a practical model to study the seeding and the spread of tau pathology and the effect of tau immunotherapy on tau pathology; and (2) that immunotherapy with 43D antibody against tau 6-18 can prevent the seeding and the spread of tau pathology, and represent a potential therapeutic treatment for AD and related tauopathies.