Dysregulated lipid metabolism is a key driver of Alzheimer’s disease (AD), yet how membrane lipid composition influences tau–membrane interaction remains poorly understood. Here, we combine single-molecule total internal reflection fluorescence microscopy with atomistic molecular dynamics (MD) simulations to elucidate the molecular basis of tau association with the supported lipid bilayer. NMR titration suggests that tau associates with negatively charged lipid headgroups via electrostatic interactions involving residues ∼120–400, which encompass the positively charged proline-rich region (PRR) and microtubule-binding repeat domains. Importantly, whereas prior studies have generally suggested that cholesterol uniformly enhances protein binding, our work reveals a much more complex and lipid-dependent mechanism: cholesterol suppresses tau binding to phosphatidylcholine–phosphatidylglycerol (PC/PG) bilayers but enhances tau binding to phosphatidylcholine–phosphatidylserine (PC/PS) bilayers. Large-scale all-atom MD simulations with a polybasic model peptide, KR8, accurately recapitulate this dichotomy at the molecular level and further reveal that the contrasting regulatory effects of cholesterol arise from lipid-dependent shifts in the preferred insertion depth of KR8, together with local conformational rearrangements of its membrane-interacting basic residues at the bilayer interface. Given that tau–membrane association contributes to aggregation and prion-like propagation, these results identify a previously unrecognized lipid-specific regulatory mechanism by which cholesterol modulates tau–membrane interactions and provide mechanistic insight into how cholesterol dysregulation contributes to AD pathogenesis.
Wu et al. (2026) studied this question.