Pseudo-Phosphorylated\nTau Forms Paired Helical Filaments\nin the Presence of High-Curvature Cholesterol-Containing Lipid Membranes

The tau protein misfolds in neurodegenerative\ndiseases such as\nAlzheimer’s disease (AD). These pathological tau aggregates\nare associated with neuronal membranes, but molecular structural information\nabout how disease-like tau fibrils interact with the lipid membrane\nis scarce. Here, we use solid-state NMR to investigate the structure\nof a tau construct bearing four AD-relevant phospho-mimetic mutations\n(4E tau) with cholesterol-containing high-curvature lipid membranes,\nwhich mimic the membrane of synaptic vesicles in neurons. We show\nthat 4E tau adopts the AD paired helical filament (PHF) fold in the\npresence of the membrane at high protein concentrations. Moreover,\nit inserts into the membrane–water interface with an orientation\nthat suggests possible bridging of multiple lipid vesicles. At lower\nprotein concentrations, moderate chemical shift changes are observed,\nindicating a perturbation of the PHF structure by the lipids. Removal\nof the phospho-mimetic mutations led to a qualitatively different\nβ-sheet conformation. These results indicate that posttranslational\nmodifications impact the tau fibril structure more strongly than lipid\nmembranes, but the membrane modulates the conformational equilibria\nof the aggregates.