(595g) Examination of the Interaction Between the Alzheimer's Disease Related Tau Protein and Model Lipid Membranes

Jones, E. M., University of New Mexico
Wiater, M., (2) Worcester Polytechnic Institute
Biernat, J., Max Planck Unit for Structural Biology
Mandelkow, E., Max Planck Unit for Structural Biology
Chi, E. Y., University of New Mexico

In this study, we characterize in depth the interaction of the Alzheimer’s disease (AD) related tau protein and model lipid membranes.  The misfolding and aggregation of the intrinsically disordered, microtubule-associated tau protein into neurofibrillary tangles is implicated in the pathogenesis of AD. However, the mechanism by which tau aggregation causes neuronal dysfunction remains unclear.  Prior lines of research suggest that tau’s interaction with the plasma membrane may modulate tau aggregation.  Our previous studies show that tau’s strong interaction with anionic lipids induces disruptions to membrane lipid packing, morphology, and structural integrity.  Binding of tau protein to lipids of the plasma membrane may play an important role in the misfolding, aggregation, and cytotoxicity of tau.  Membrane lipids may provide a favorable local environment which facilitates misfolding and aggregation of tau protein.  Membrane permeabilization may also 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 investigate tau’s propensity to interact with membranes to elucidate the disruptive effects these interactions induce in the membrane.  To examine this interaction, we use Surface Plasmon Resonance (SPR) to study the binding of tau protein constructs to lipid bilayers of differing charge composition.  SPR allows for both qualitative and quantitative data on interactions of proteins with lipid membranes.  We obtain and compare equilibrium and kinetic binding parameters for tau construct ligands interacting with both pure zwitterionic and anionic lipid containing systems.  To further investigate we also perform vesicle dye leakage experiments using tau constructs and vesicles of varying lipid composition.  Using these results, we comprehensively study the role of lipid bilayer composition on tau-lipid membrane binding and membrane disruption.