Structures of AT8 and PHF1 Phospho-Mimetic Tau: Insights Into the Posttranslational Modification Code of Tau Amyloid Formation

Abstract

The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that this posttranslational modification may induce pathological tau aggregation. Tau is also phosphorylated in normal developing brains. To investigate how tau phosphorylation induces amyloid fibrils, here we report the atomic structures of two phospho-mimetic full-length tau fibrils assembled without anionic cofactors. One set of phospho-mimetic mutations is targeted by the antibody AT8, while the other set is targeted by the antibody PHF1. Solid-state NMR and cryo-electron microscopy data reveal that AT8 tau forms a unique triangular fibril core that encompasses the entire C-terminal third of the protein, whereas PHF1 tau forms a triple-stranded core. These results demonstrate that specific post-translational modifications induce structurally specific tau aggregates. We propose that these aggregates may evolve into pathological filaments under suitable cellular conditions or remain as transient species in normal brains.