| AVS 57th International Symposium & Exhibition | |
| Biomaterial Interfaces | Wednesday Sessions |
| Session BI1-WeM |
| Session: | Biomolecules at Interfaces |
| Presenter: | E.Y. Chi, University of New Mexico |
| Authors: | E.Y. Chi, University of New Mexico J. Majewski, Los Alamos National Laboratory E. Mandelkow, Max Planck Unit for Structural Molecular Biology, Germany K.Y. Lee, University of Chicago |
| Correspondent: | Click to Email |
The misfolding and aggregation of the amyloid-beta (Ab) peptide and tau protein into fibrillar deposits are linked to the pathogenesis of Alzheimer’s disease (AD). However, the molecular basis of the early events during the aggregation process and the nature of the structural fluctuations that triggers the misfolding and association of Ab and tau remain poorly understood. The lipid membrane interface has been implicated to mediate the fibrillogenesis of both proteins. Using model lipid membranes, we studied the nature and mode of lipid-protein interactions and characterized the effect of these interactions on the conformation and assembly of Ab and tau.
Both Ab and tau exhibit strong interactions with membranes composed of charged lipids, but interact weakly with zwitterionic lipids. To elucidate the molecular-scale structural details of Ab-membrane association, we used complementary X-ray and neutron scattering techniques (grazing-incidence X-ray diffraction, X-ray reflectivity, and neutron reflectivity) to investigate in situ the association of Ab with lipid monolayers at the air/water interface composed of either the negatively charged lipid DPPG, the zwitterionic lipid DPPC, or the cationic lipid DPTAP at the air/water interface. We found that the anionic lipid DPPG uniquely induced crystalline ordering of Ab at the membrane surface that closely mimicked the beta-sheet structures in fibrils, revealing an intriguing templated ordering effect of DPPG on Ab. Furthermore, incubating Ab with lipid vesicles containing the anionic lipid POPG induced the formation of amyloid fibrils, confirming that the templated ordering of Ab at the membrane surface seeded fibril formation. By measuring the interaction between different tau constructs (hTau40, K18 and K32) with membranes composed of different lipids, our data showed that tau’s C-terminus, the microtubule binding domain, is responsible for its association with the lipid membrane. Moreover, hyperphophorylation which is an early and critical event in the pathogenesis of AD, as mimicked by a tau mutant, did not prevent tau from binding to lipid membrane.
Our study provides a detailed molecular-scale characterization of the early structural fluctuation and assembly events that may trigger the misfolding and aggregation of Ab in vivo. Our study suggests that the “soft”, intrinsically unfolded nature of both Ab and tau can give rise to rich dynamic behaviors at interfaces, such as the lipid membrane interface. Our data implicate that the adsorption of Ab and tau to anionic lipids in the cell membrane may serve as an in vivo mechanism of templated aggregation and drive the pathogenesis of AD.