(525d) Tau Misfolding and Assembly at Lipid Membrane Interfaces

Authors: 
Chi, E. Y., University of New Mexico
Jones, E. M., University of New Mexico
Junghans, A., Los Alamos Neutron Science Center, Los Alamos National Laboratory
Biernat, J., Max Planck Unit for Structural Biology
Mandelkow, E., Max Planck Unit for Structural Biology
Majewski, J., Los Alamos National Laboratory
Interaction between the microtubule associated, intrinsically disordered, tau protein with the lipid membrane has been shown to induce tau structural compaction and membrane disruption, suggesting possible membrane-mediated pathways for tau aggregation and toxicity in neurodegenerative tauopathies, including Alzheimerâ??s disease (AD) and familial frontotemporal dementia. In this study, we examined the effects of hyperphosphorylation, an early event in AD pathogenesis, and tau domain composition on tau-membrane interactions using the psudo-phosphorylation mutant hTau40/3Epi and the repeat domain of tau K18, which lacks the projection domain, respectively. Complementary X-ray and neutron scattering techniques were used to resolve Ã?-level structural details of tau association with model lipid monolayers at the air/water interface and quartz supported lipid bilayers. Results show that neither hyperphosphorylation nor truncation of the tau projection domain significantly affected the tauâ??s intrinsic surface activity or membrane interaction. The mutant and K18 were highly surface active and exhibited selective, yet strong interactions with anionic lipid membranes. Furthermore, binding of the tau proteins to lipid membranes induced tau structural compaction of and disrupted membrane morphology, lipid packing, and structural integrity. Results from this study thus show that membrane-based pathways that induce tau aggregation and lead to toxicity are insensitive towards details of the amino acid composition of the tau protein, and could serve as a general mechanism by which tau misfolds and aggregate into pathogenic aggregates.