(407a) 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.