Interaction of full-length Tau with negatively charged lipid membranes leads to polymorphic aggregates.

The Tau protein is implicated in various diseases collectively known as tauopathies, including Alzheimer's disease and frontotemporal dementia. The precise mechanism underlying Tau pathogenicity remains elusive. Recently, the role of lipids has garnered interest due to their implications in Tau aggregation, secretion, uptake, and pathogenic dysregulation. Previous investigations have highlighted critical aspects: (i) Tau's tendency to aggregate into fibers when interacting with negatively charged lipids, (ii) its ability to form structured species upon contact with anionic membranes, and (iii) the potential disruption of the membrane upon Tau binding. In this study, we examine the disease-associated P301L mutation of the 2N4R isoform of Tau and its effects on membranes composed on phosphatidylserine (PS) lipids. Aggregation studies and liposome leakage assays demonstrate Tau's ability to bind to anionic lipid vesicles, leading to membrane disruption. Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) reveals the accumulation of Tau on the membrane surface without protein insertion, structuration, or lipid removal. Plasmon waveguide resonance (PWR) demonstrates a strong binding of Tau on PS bilayers with an apparent in the micromolar range, indicating the deposition of a thick protein layer. Atomic force microscopy (AFM) real-time imaging allows the observation of partial lipid solubilization and the deposition of polymorphic aggregates in the form of thick patches and fibrillary structures resembling amyloid fibers, which could grow from a combination of extracted anionic phospholipids from the membrane and Tau protein. This study deepens our understanding of full-length Tau's multifaceted interactions with lipids, shedding light on potential mechanisms leading to the formation of pathogenic Tau assemblies.