Two novel tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce tau pathology.

Aggregated tau proteins are hallmarks of Alzheimer's disease and other tauopathies. Recent studies from our group and others have demonstrated that both active and passive immunizations reduce tau pathology and prevent cognitive decline in transgenic mice. To determine the efficacy and safety of targeting a phospho epitope versus a non-phospho epitope, we developed two novel monoclonal antibodies (mAbs) with these distinct properties against the 396/404 region of the tau protein. The two mAbs significantly reduced phosphorylated soluble tau in long-term brain slice cultures without apparent toxicity, suggesting the therapeutic importance of targeting the 396/404 region, regardless of its phosphorylation status. In mechanistic studies, we found that neurons were the primary cell type that internalized the mAbs, whereas a small amount of mAbs was taken up by microglia cells. Within neurons, the two mAbs were highly colocalized with distinct pathological tau markers, indicating their affinity towards different stages or forms of pathological tau. Moreover, the mAbs were largely co-localized with endosomal/lysosomal markers, and partially co-localized with autophagy pathway markers. Additionally, the Fab fragments of the mAbs were able to enter neurons, but unlike the whole antibodies, the Fab fragments were not specifically localized in pathological neurons. In summary, our tau mAbs were safe and efficient to clear pathological tau in a brain slice model. Fc-receptor mediated endocytosis and the endosome/autophagosome/lysosome system are likely to have a critical role in antibody-mediated clearance of tau pathology.