The aggregation of the intrinsically disordered
tau protein into highly ordered β-sheet-rich fibrils is implicated in the pathogenesis of a range of
neurodegenerative disorders. The mechanism of tau fibrillogenesis remains unresolved, particularly early events that trigger the misfolding and assembly of the otherwise soluble and stable tau. We investigated the role the
lipid membrane plays in modulating the aggregation of three tau variants, the largest
isoform hTau40, the truncated construct
K18, and a hyperphosphorylation-mimicking mutant hTau40/3Epi. Despite being charged and soluble, the
tau proteins were also highly surface active and favorably interacted with anionic
lipid monolayers at the air/water interface. Membrane binding of tau also led to the formation of a macroscopic, gelatinous layer at the air/water interface, possibly related to tau phase separation. At the molecular level, tau assembled into oligomers composed of ~ 40
proteins misfolded in a β-sheet conformation at the membrane surface, as detected by in situ
synchrotron grazing-incidence X-ray diffraction. Concomitantly, membrane morphology and
lipid packing became disrupted. Our findings support a general tau aggregation mechanism wherein tau's inherent surface activity and favorable interactions with anionic
lipids drive tau-membrane association, inducing misfolding and self-assembly of the disordered tau into β-sheet-rich oligomers that subsequently seed fibrillation and deposition into diseased tissues.