Synaptically preferred anti‐tau antibodies reduce in vitro tau seeding and in vivo neuronal loss

Background In Alzheimer’s Disease (AD) brains, pathological tau species accumulate at the synapses where the cell‐to‐cell transmission of tau has been experimentally demonstrated. Method A series of assays including: dot‐blot assay of synaptic versus cytosolic fractions, brain immunohistochemistry (IHC), HEK cell‐based tau seeding assay, mass spectrometry‐based epitope mapping and in vivo rTg4510 animal efficacy study were used to identify anti‐tau antibodies for therapeutic purposes. Result APRINOIA has characterized 12 anti‐tau antibodies bind to synaptic tau species isolated from AD brain tissues. These synaptic preferred anti‐tau antibodies were not only highly specific to pathological tau species in AD brains, but also exhibited diverse subcellular localization in rTg4510 tau transgenic mouse brains. Among them, we focused on 2 antibodies, APNmAb005 and 037. For 005, it localized at axodendritic compartments in the hippocampi of 3‐mo rTg4510 brains and was found to bind conformational epitopes in the mid‐region of tau protein. On the other hand, 037 localized in the somatic compartments with a conformational epitope in the repeat domain of tau. Moreover, both antibodies could block tau seeding from the rTg4510 mouse brain lysates or from the secreted tau of rTg4510 synaptoneurosomes. A 3‐month efficacy study was performed in rTg4510 animals for 005 and significant reduction of neuronal loss was observed. Conclusion The therapeutic potentials of anti‐tau antibodies are not judged by the location of epitopes or sub‐cellular localization, but by their abilities to recognize synaptically localized tau in AD brains.