P2‐387: Phospho‐tau–specific vaccine for the treatment of tau pathology

The brain of patients with advancing Alzheimer's disease is characterized by two hallmarks, beta-amyloid plaques and neurofibrillary tangles (NFT) composed of hyper-phosphorylated Tau. The excess of amyloid and hyperphosphorylated Tau protein are both present as a spectrum of misfolded protein-aggregates. Immunotherapy can alleviate the pathological impact of protein-aggregates, while also contributing to our molecular understanding of these neurotoxic species. Immunotherapy has shown success in animal models and the interest to target phosphorylated Tau is growing. Tauopathy (Tau.P301L transgenic) and wild-type mice were immunized with a liposome-based Tau vaccine. Immunoresponse was tested by specific immunostaining of tauopathy brains and by target-specific immunodetection methods. Vaccine efficacy was measured by probing pathological phospho-Tau epitopes in brain homogenate of treated mice by Western-blots. Additionally, we used a variety of immunobased techniques to further characterize the vaccine response. A liposome-based vaccine technology was used (Muhs et al., 2007) to generate a phospho Tau vaccine that induced a high antisera response in Tau.P301L tauopathy and wild-type mice (Theunis et al., AAIC 2011 presentation), without eliciting an adverse immune reaction. Specific ELISA demonstrated high and stable antibody titers against phospho-Tau-peptides as opposed to no reaction to non-phosphorylated Tau. The high specificity for pathological tau was visualized by TAUPIR on brain sections from Tau.P301LxGSK3 (biGT) mice with proven tauopathy (Terwel et al, 2008). Compared to control treatment, vaccination resulted in a significant reduction of insoluble phospho-Tau epitopes, with a high specificity for pathological phospho-Tau species. These data support previous findings on the potential of liposomal Tau vaccines to modify pathological Tau accumulation and suggest that this vaccine approach has the potential to become a promising therapy, not only for the treatment of AD but also for other Tau-mediated neurodegenerative diseases.