A Novel Pathogenic Tau Conformer Playing Part in Tau Pathology in Human Neurons Upon Aging Stress

Abstract Alzheimer’s disease (AD), is the most prevalent cause of dementia, with no effective treatment thus far. It is clear that tau protein hyperphosphorylation is the major pathogenic process, leading to neurodegeneration upon AD. It has been previously shown that tau phosphorylation at Thr231 is of crucial importance in tauopathy process. It was reported that pT231-tau in the cis conformation is the early driver of tau pathogenicity in the tauopathy mouse models. In this study, we identified gauche P-tau pathology (a novel P-tau conformer) in human postmortem brain tissue and as well as induced pluripotent stem cell (iPSC) derived neurons from AD patients as the neurotoxic pT231-tau conformer. We observed gauche P-tau levels dramatically increase in neurons under aging stress which disrupts the microtubule network, propagates to other neurons, and ultimately leads to apoptosis and cell death. Moreover, while cis p-tau depletion using respective monoclonal antibody suppressed neurodegeneration in mouse neurons, gauche p-tau elimination using respective monoclonal antibody stopped neurodegeneration in the human AD cultured neurons. Taken these together, we concluded that gauche p-tau is the leading cause of neuronal cell death in human neurons, and the anti gauche p-tau antibody could be introduced as an efficient therapeutic for blocking neurodegeneration upon AD.