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Tau oligomers as a therapeutic target for Alzheimer's disease

      Background: The majority of neurodegenerative tauopathies are associated with the pathological accumulation of additional amyloid proteins, notably amyloid-β in Alzheimer's disease (AD). Studies have shown that intermediate aggregates known as oligomers are the most toxic species in disease. The common toxic factor in these diseases, the tau oligomer, is a promising therapeutic target in mixed pathology diseases. We have recently shown that passive immunotherapy with a novel tau oligomer-specific antibody is effective in two different pure tauopathy models, P301L and Htau mice. Here we directly test the interaction between tau and amyloid oligomers and the efficacy of anti-tau oligomer immunotherapy in a model of AD.
      Methods: We have evaluated brain tissue and oligomers derived from AD patients for the interaction between amyloid proteins and tau using biochemical and immunohistochemical analysis with our novel oligomer-specific antibodies. To investigate the efficacy of immunotherapy with anti-tau oligomer monoclonal antibody (TOMA) in an AD model, we examined the behavior and pathology of treated Tg2576 mice.
      Results: We found that Aβ oligomers can seed the aggregation of tau in vitro and are colocalized in disease, forming hybrid oligomers. Treatment with TOMA reverses cognitive detriment and decreases tau oligomer levels in Tg2576 mice, while increasing stable Aβ plaque levels.
      Conclusions: Our results suggest that oligomeric Aβ has a synergistic relationship with tau oligomers. This combined with passive immunotherapy results suggest that tau oligomers are a good therapeutic target in AD and potentially in other mixed pathology tauopathies.