The aggregation of the tau protein plays a significant role in Alzheimer's disease, and the tau R3-R4 domain spanning residues 306-378 was shown to form the amyloid fibril core of a full-length tau. The conformations of the tau R3-R4 monomer in the bulk solution and at the surface of membranes are unknown. In this study, we address these questions by means of atomistic molecular dynamics. The simulations in the bulk solution show a very heterogeneous ensemble of conformations with low β and helical contents. The tau R3-R4 monomer has the propensity to form transient β-hairpins within the R3 repeat and between the R3 and R4 repeats and parallel β-sheets spanning the R3 and R4 repeats. The simulations also show that the surface of the membrane does not induce β-sheet insertion and leads to an ensemble of structures very different from those in the bulk solution. They also reveal the dynamical properties of the membrane-bound state of the tau R3-R4 monomer, enabling insertion of the residues 306-318 and 376-378.

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Molecular Dynamics Simulations of the Tau R3-R4 Domain Monomer in the Bulk Solution and at the Surface of a Lipid Bilayer Model.

The conversion of intrinsically disordered Tau to highly ordered amyloid aggregates is associated with a wide range of neurodegenerative diseases termed tauopathies. The presence of lipid bilayer membranes is a critical factor that accelerates the abnormal aggregation of Tau protein. However, the lipid membrane-induced conformational changes of Tau and the mechanism for the accelerated fibrillation remain elusive. In this study, single-molecule Förster resonance energy transfer (smFRET) and fluorescence correlation spectroscopy (FCS) were applied to detect the conformational changes and intermolecular interactions of full-length Tau in the presence of different concentrations of 1,2-dimyristoyl-sn-glycero-3-phosphatidylserine (DMPS) vesicles. The results show that the conformation of Tau becomes expanded with opening of the N-terminal and C-terminal domains of Tau upon binding to DMPS. At low DMPS concentrations, Tau forms oligomers with a partially extended conformation which facilitates the amyloid fibrillization process. At high DMPS concentrations, Tau monomer binds to lipid membranes in a fully expanded conformation at low density thus inhibiting intermolecular aggregation. Our study reveals the underlying mechanisms by which lipid membranes influence amyloid formation of Tau, providing a foundation for further understanding of the pathogenesis and physiology of the interplay between Tau protein and lipid membranes.

Distinct lipid membrane-mediated pathways of Tau assembly revealed by single-molecule analysis.

A tau R3-R4 domain spanning residues 306-378 was shown to form an amyloid fibril core of a full-length tau in the brain of patients with Alzheimer's disease. Recently, we studied the dynamics of a tau R3-R4 monomer at the surface of a lipid bilayer model and revealed deep insertion of the amino acids spanning the PHF6 motif (residues 306-311) and its flanking residues. Here, we explore the membrane-associated conformational ensemble of a tau R3-R4 dimer by means of atomistic molecular dynamics. Similar to the monomer simulation, the R3-R4 dimer has the propensity to form β-hairpin-like conformation. Unlike the monomer, the dimer shows insertion of the C-terminal R4 region and transient adsorption of the PHF6 motif. Taken together, these results reveal the multiplicity of adsorption and insertion modes of tau into membranes depending on its oligomer size.

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Molecular Dynamics Simulations of the Tau Amyloid Fibril Core Dimer at the Surface of a Lipid Bilayer Model: I. In Alzheimer's Disease.

The self-aggregation of tau, a microtubule-binding protein, has been linked to the onset of Alzheimer’s Disease. Recent studies indicate that the disordered tau aggregates, or oligomers, are more toxic than the ordered fibrils found in the intracellular neurofibrillary tangles of tau. At present, details of tau oligomer interactions with lipid rafts, a model of neuronal membranes, are not known. Using molecular dynamics simulations, the lipid-binding events, membrane-damage, and protein folding of tau oligomers on various lipid raft surfaces were investigated. Tau oligomers preferred to bind to the boundary domains (Lod) created by the coexisting liquid-ordered (Lo) and liquid-disordered (Ld) domains in the lipid rafts. Additionally, stronger binding of tau oligomers to the ganglioside (GM1) and phosphatidylserine (PS) domains, and subsequent protein-induced lipid chain order disruption and beta-sheet formation were detected. Our results suggest that GM1 and PS domains, located exclusively in the outer and inner leaflets, respectively, of the neuronal membranes, are specific membrane domain targets, whereas the Lod domains are non-specific targets, of tau oligomers binding to neurons. The molecular details of these specific and non-specific tau bindings to lipid rafts may provide new insights into understanding membrane-associated tauopathies leading to Alzheimer’s Disease.

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Exploring Membrane Binding Targets of Disordered Human Tau Aggregates on Lipid Rafts Using Multiscale Molecular Dynamics Simulations

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer’s Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between Aβ oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic Aβ/tau cross interactions are not fully understood. Here, we discuss the common features of Aβ and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both Aβ and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on Aβ and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of Aβ and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct Aβ/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic Aβ/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics.

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Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease?

Tau misfolding and assembly is linked to a number of neurodegenerative diseases collectively described as tauopathies, including Alzheimer's disease (AD) and Parkinson's disease. Anionic cellular membranes, such as the cytosolic leaflet of the plasma membrane, are sites that concentrate and neutralize tau, primarily due to electrostatic interactions with tau's microtubule binding repeat domain (RD). In addition to electrostatic interactions with lipids, tau also has interactions with membrane proteins, which are important for tau's cellular functions. Tau also interacts with lipid tails to facilitate direct translocation across the membrane and can form stable protein-lipid complexes involved in cell-to-cell transport. Concentrated tau monomers at the membrane surface can form reversible condensates, change secondary structures, and induce oligomers, which may eventually undergo irreversible crosslinking and fibril formation. These β-sheet rich tau structures are capable of disrupting membrane organization and are toxic in cell-based assays. Given the evidence for relevant membrane-based tau assembly, we review the emerging hypothesis that polyanionic membranes may serve as a site for phase-separated tau condensation. Membrane-mediated phase separation may have important implications for regulating tau folding/misfolding, and may be a powerful mechanism to spatially direct tau for native membrane-mediated functions.

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Crystal M Vander Zanden

Papers

Tau and Membranes: Interactions That Promote Folding and Condensation.