A Novel Phosphorylated Tau Conformer Implicated in the Tauopathy Pathogenesis of Human Neurons.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cult

SUBMITTER: Tofigh N 

PROVIDER: S-EPMC12025006 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature