Interaction of Tau Protein with Model Lipid Membranes Induces Membrane Disruption

The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of Alzheimer's disease. However, the mechanism by which tau aggregation causes neuronal dysfunction remains unclear.  Recent work has shown that lipid membrane permeabilization may serve as a pathway by which protein aggregates exert toxicity through cell membrane disruption, resulting in the alteration of ion homeostasis and disregulation of neuronal signal transduction.We investigated tau's propensity to interact with membranes and elucidated the disruptive structural perturbations these interactions induce in the membrane. We show that tau selectively inserts into anionic DMPG lipid monolayers at the air/water interface over neutrally charged membranes. Upon insertion into DMPG monolayer, tau disrupts the morphology of lipid condensed domains in the membrane. On the molecular scale, grazing incidence X-ray diffraction data show that tau insertion disrupts the packing of lipid tails. Neutron reflectivity data show that tau completely disrupts supported DMPG bilayers while leaving the neutral DPPC bilayer intact.  To further investigate whether tau induced membrane structural changes lead to permeabilization, we also perform vesicle dye leakage experiments, which show that tau can induce dye leakage from vesicles containing anionic lipids.  Our results indicate that tau's strong interaction with anionic lipids induces disruptions to membrane lipid packing, morphology, and structural integrity, suggesting possible membrane-based mechanisms of tau toxicity in neurodegenerative diseases.