Abstract
The intrinsically disordered protein tau aggregates into β-sheet amyloid fibrils that spread in human brains afflicted with Alzheimer's disease and other neurodegenerative diseases. Tau interaction with lipid membranes might play a role in the formation and spreading of these pathological aggregates. Here we investigate the conformation and assembly of membrane-induced tau aggregates using solid-state NMR and transmission electron microscopy. A tau construct that encompasses the microtubule-binding repeats and a proline-rich domain is reconstituted into cholesterol-containing phospholipid membranes. 2D (13)C-(13)C correlation spectra indicate that tau converted from a random coil to a β-sheet conformation over weeks. Small unilamellar vesicles (SUVs) cause different equilibrium conformations from large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs). Importantly, SUV-bound tau developed long fibrils that exhibit the characteristic β-sheet chemical shifts of Tyr310 in heparin-fibrillized tau. In comparison, LUVs and MLVs do not induce fibrils but cause different β-sheet aggregates. Lipid-protein correlation spectra indicate that these tau aggregates reside at the membrane-water interface, without inserting into the middle of the lipid bilayer. Removal of cholesterol from the SUVs abolished the fibrils, indicating that both membrane curvature and cholesterol are required for tau fibril formation. These results have implications for how lipid membranes might nucleate tau aggregates.