Tau protein phosphorylation at Thr175 initiates fibril formation via accessibility of the N‐terminal phosphatase‐activating domain

One of the neuropathological hallmarks of the tauopathies is the formation of neuronal cytoplasmic inclusions and fibrils of microtubule-associated tau protein (tau). The phosphorylation of Thr(175) of tau (pThr(175) tau) appears to be sufficient for fibril formation in vitro and in vivo, but the mechanism by which this initiates fibril formation is unknown. Using transient transfections of tau mutants into HEK293T cells, we determined that the phosphorylation of Thr(175) leads to exposure of the tau N-terminal phosphatase-activating domain (PAD). The exposed PAD is known to interact with protein phosphatase-1 (PP1) resulting in glycogen synthase kinase 3beta (GSK3beta) activation. In vivo, a single traumatic controlled cortical injury in rats also resulted in the phosphorylation of Thr(175) and increased exposure of tau PAD followed by pathological tau fibril formation. Taken together, these data suggest that neurotoxicity may be precipitated by phosphorylation at Thr(175) and subsequent tau PAD exposure, GSK3beta activation and tau fibril formation.