Tau antibody 77G7 targeting microtubule binding domain suppresses oligomeric tau to seed tau aggregation

Abstract

AbstractBackgroundNeurofibrillary tangle (NFT) of hyperphosphorylated tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. Tau lesion starts in the trans‐entorhinal cortex, from where it spreads to limbic regions, followed by neocortical areas. The regional distribution of NFTs associates with the progression of AD. Accumulating evidence suggests that proteopathic tau can seed tau aggregation in a prion‐like fashion in vitro and in vivo. Inhibition of the seeding activity of proteopathic tau could provide a potential therapeutic opportunity to block the propagation of tau pathology. In the present study, we investigated the role of 77G7, a monoclonal tau antibody to the microtubule‐binding repeats, in the seeding activity of proteopathic tau.MethodAffinity of 77G7 to various tau strains, including oligomeric tau (AD O‐tau), sarkosyl insoluble tau (SI‐tau), and heat stable normal tau (HS‐tau) isolated from frozen autopsied AD brains by sedimentation, was analyzed by immuno‐dot‐blots. Seeding activity of AD O‐tau was accessed by the level of aggregated tau in vitro and in cultured cells and by overlay capture assay. Tau pathology in human tau transgenic mice was induced by hippocampal injection of AD O‐tau. 77G7 was mixed with AD O‐tau or was intravenously administrated weekly for 6 weeks started one week prior to AD O‐tau injection. Tau phosphorylation and tau pathology were analyzed by immunohistochemical staining and Western blots 8‐10 weeks after AD O‐tau injection.ResultWe found that 77G7 had a higher affinity toward aggregated tau strains than un‐aggregated tau derived from AD brain. 77G7 inhibited the internalization of tau aggregates by cells, blocked AD O‐tau to capture normal tau and to seed tau aggregation in vitro and in cultured cells. AD O‐tau induced tau pathology in hippocampus of 3xTg‐AD mice was reduced by mixing 77G7 with AD O‐tau. Intravenous administration of 77G7 ameliorated site‐specific hyperphosphorylation of tau induced by AD O‐tau in the hippocampi of Tg/hTau mice.ConclusionThese findings indicate that 77G7 can effectively suppress the seeding activity of AD O‐tau and thus, could be developed as a potential immunotherapeutic drug to inhibit the propagation of tau pathology in AD and related tauopathies.