Full-length Tau disrupts fluid zwitterionic supported lipid bilayers.

The Tau protein is involved in several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Under physiological conditions, Tau binds to microtubules and participates in neuronal integrity. Under pathological conditions, Tau misfolds and aggregates into insoluble amyloid fibers, ultimately leading to neuronal death. Most studies have focused on Tau aggregation promoted by negatively charged cofactors such as anionic lipids or polyanions, while its interactions with neutral membrane components have received less attention. Notably, phosphatidylcholine (PC), the most abundant zwitterionic phospholipid in the plasma membrane, has been detected within Tau aggregates in vivo, and Tau can directly interact with membranes through their lipid or protein components. Here, we investigated the interaction between Tau and PC-containing model membranes using polarized infrared spectroscopy and atomic force microscopy. Supported bilayers composed of DOPC, mixed DOPC:DPPC, and DPPC containing cholesterol were used to modulate membrane fluidity. Our results show that Tau binds to and perturbs PC membranes only when sufficient fluidity is present, while retaining its native structural conformation. These findings highlight a previously underexplored aspect of Tau-membrane interactions and suggest that the physical state of the membrane may play a key role in modulating Tau pathogenicity.