Binding Sites of a PET Ligand in Tau Fibrils with the Alzheimer's Disease Fold from F and C Solid-State NMR.

Aggregation of the tau protein into cross-β amyloid fibrils is a hallmark of Alzheimer's disease (AD) and many other neurodegenerative disorders. Developing small molecules that bind these tau fibrils is important for the diagnosis and treatment of tauopathies. Here, we report the binding sites of a positron emission tomography (PET) ligand, PI-2620, to a recombinant tau construct that adopts the C-shaped AD fold.

Structures of ΔD421 Truncated Tau Fibrils.

The microtubule-associated protein tau aggregates into pathological β-sheet amyloid fibrils in Alzheimer's disease (AD) and other neurodegenerative diseases. In these aggregates, tau is chemically modified, including abnormal hyperphosphorylation and truncation. Truncation after D421 in the C-terminal domain occurs at early stages of AD.

Pseudo-Phosphorylated Tau Forms Paired Helical Filaments in the Presence of High-Curvature Cholesterol-Containing Lipid Membranes.

The tau protein misfolds in neurodegenerative diseases such as Alzheimer's disease (AD). These pathological tau aggregates are associated with neuronal membranes, but molecular structural information about how disease-like tau fibrils interact with the lipid membrane is scarce. Here, we use solid-state NMR to investigate the structure of a tau construct bearing four AD-relevant phospho-mimetic mutations (4E tau) with cholesterol-containing high-curvature lipid membranes, which mimic the membrane of synaptic vesicles in neurons.

Alzheimer's disease seeded tau forms paired helical filaments yet lacks seeding potential.

Alzheimer's disease (AD) and many other neurodegenerative diseases are characterized by pathological aggregation of the protein tau. These tau aggregates spread in a stereotypical spatiotemporal pattern in the brain of each disease, suggesting that the misfolded tau can recruit soluble monomers to adopt the same pathological structure. To investigate whether recruited tau indeed adopts the same structure and properties as the original seed, here we template recombinant full-length 0N3R tau, 0N4R tau, and an equimolar mixture of the two using sarkosyl-insoluble tau extracted from AD brain and determine the structures of the resulting fibrils using cryoelectron microscopy.

Milligram-scale assembly and NMR fingerprint of tau fibrils adopting the Alzheimer's disease fold.

In the Alzheimer's disease (AD) brain, the microtubule-associated protein tau aggregates into paired helical filaments in which each protofilament has a C-shaped conformation. In vitro assembly of tau fibrils adopting this fold is highly valuable for both fundamental and applied studies of AD without requiring patient-brain extracted fibrils. To date, reported methods for forming AD-fold tau fibrils have been irreproducible and sensitive to subtle variations in fibrillization conditions.

Selective Detection of Intermediate-Amplitude Motion by Solid-State NMR.

The coexistence of rigid and mobile molecules or molecular segments abounds in biomolecular assemblies. Examples include the carbohydrate-rich cell walls of plants and intrinsically disordered proteins that contain rigid β-sheet cores. In solid-state nuclear magnetic resonance (NMR) spectroscopy, dipolar polarization transfer experiments are well suited for detecting rigid components, whereas scalar-coupling experiments are well suited for detecting highly mobile components.

Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation.

The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that this posttranslational modification (PTM) may induce tau aggregation. Tau is also phosphorylated in normal developing brains.

Structure of the nonhelical filament of the Alzheimer's disease tau core.

The microtubule-associated protein tau aggregates into neurofibrillary tangles in Alzheimer's disease (AD). The main type of aggregates, the paired helical filaments (PHF), incorporate about 20% of the full-length protein into the rigid core. Recently, cryo-electron microscopy data showed that a protease-resistant fragment of tau (residues 297-391) self-assembles in vitro in the presence of divalent cations to form twisted filaments whose molecular structure resembles that of AD PHF tau [S.

Amyloid fibril structures of tau: Conformational plasticity of the second microtubule-binding repeat.

The intrinsically disordered protein tau associates with microtubules in neurons but aggregates into cross-β amyloid fibrils that propagate in neurodegenerative brains. Different tauopathies have different structures for the rigid fibril core. To understand the molecular basis of tau assembly into different polymorphs, here we use solid-state nuclear magnetic resonance (NMR) spectroscopy to determine the structure of a tau protein that includes all microtubule-binding repeats and a proline-rich domain.

Membrane-induced tau amyloid fibrils.

The intrinsically disordered protein tau aggregates into β-sheet amyloid fibrils that spread in human brains afflicted with Alzheimer's disease and other neurodegenerative diseases. Tau interaction with lipid membranes might play a role in the formation and spreading of these pathological aggregates. Here we investigate the conformation and assembly of membrane-induced tau aggregates using solid-state NMR and transmission electron microscopy.

Solid-State NMR F-H-N Correlation Experiments for Resonance Assignment and Distance Measurements of Multifluorinated Proteins.

Several solid-state NMR techniques have been introduced recently to measure nanometer distances involving F, whose high gyromagnetic ratio makes it a potent nuclear spin for structural investigation. These solid-state NMR techniques either use F correlation with H or C to obtain qualitative interatomic contacts or use the rotational-echo double-resonance (REDOR) pulse sequence to measure quantitative distances. However, no NMR technique is yet available for disambiguating H-F distances in multiply fluorinated proteins and protein-ligand complexes.

Mechanism for selective binding of aromatic compounds on oxygen-rich graphene nanosheets based on molecule size/polarity matching.

Selective binding of organic compounds is the cornerstone of many important industrial and pharmaceutical applications. Here, we achieved highly selective binding of aromatic compounds in aqueous solution and gas phase by oxygen-enriched graphene oxide (GO) nanosheets via a previously unknown mechanism based on size matching and polarity matching. Oxygen-containing functional groups (predominately epoxies and hydroxyls) on the nongraphitized aliphatic carbons of the basal plane of GO formed highly polar regions that encompass graphitic regions slightly larger than the benzene ring.

Microtubule-binding core of the tau protein.

The protein tau associates with microtubules to maintain neuronal health. Posttranslational modifications of tau interfere with this binding, leading to tau aggregation in neurodegenerative disorders. Here, we use solid-state nuclear magnetic resonance (NMR) to investigate the structure of the microtubule-binding domain of tau.

Fluent molecular mixing of Tau isoforms in Alzheimer's disease neurofibrillary tangles.

Alzheimer's disease (AD) is defined by intracellular neurofibrillary tangles formed by the microtubule-associated protein tau and extracellular plaques formed by the β-amyloid peptide. AD tau tangles contain a mixture of tau isoforms with either four (4R) or three (3R) microtubule-binding repeats. Here we use solid-state NMR to determine how 4R and 3R tau isoforms mix at the molecular level in AD tau aggregates.

Privacy-Preserving Multi-Class Support Vector Machine Model on Medical Diagnosis.

With the rapid development of machine learning in the medical cloud system, cloud-assisted medical computing provides a concrete platform for remote rapid medical diagnosis services. Support vector machine (SVM), as one of the important algorithms of machine learning, has been widely used in the field of medical diagnosis for its high classification accuracy and efficiency. In some existing schemes, healthcare providers train diagnostic models with SVM algorithms and provide online diagnostic services to doctors.

Binding Sites of a Positron Emission Tomography Imaging Agent in Alzheimer's β-Amyloid Fibrils Studied Using F Solid-State NMR.

Amyloid imaging by positron emission tomography (PET) is an important method for diagnosing neurodegenerative disorders such as Alzheimer's disease. Many C- and F-labeled PET tracers show varying binding capacities, specificities, and affinities for their target proteins. The structural basis of these variations is poorly understood.

Physicochemical Changes in Biomass Chars by Thermal Oxidation or Ambient Weathering and Their Impacts on Sorption of a Hydrophobic and a Cationic Compound.

This study examined conditions that mimic oxidative processes of biomass chars during formation and weathering in the environment. A maple char prepared at the single heat treatment temperature of 500 °C for 2 h was exposed to different thermal oxidation conditions or accelerated oxidative aging conditions prior to sorption of naphthalene or the dication paraquat. Strong chemical oxidation (SCO) was included for comparison.

Inclusion of the C-Terminal Domain in the β-Sheet Core of Heparin-Fibrillized Three-Repeat Tau Protein Revealed by Solid-State Nuclear Magnetic Resonance Spectroscopy.

Many neurodegenerative diseases such as Alzheimer's disease are characterized by pathological β-sheet filaments of the tau protein, which spread in a prion-like manner in patient brains. To date, high-resolution structures of tau filaments obtained from patient brains show that the β-sheet core only includes portions of the microtubule-binding repeat domains and excludes the C-terminal residues, indicating that the C-terminus is dynamically disordered. Here, we use solid-state NMR spectroscopy to identify the β-sheet core of full-length 0N3R tau fibrillized using heparin.

Coordinating capillary infiltration with anodic oxidation: a multi-functional strategy for electrochemical fabrication of graphene.

Electrochemical exfoliation of graphite stands out as a promising alternative to the existing methods for scalable graphene fabrication. However, factors governing the electrochemical process and the underlying mechanism are complex and how to effectively control the exfoliation process is far from completely clear despite many attempts in previous works. Herein, for the first time, capillary infiltration, anodic oxidation and their dependence on temperature were found to be critical in determining the electrolyte infiltration and the anodic oxidation process.

Hydration and Dynamics of Full-Length Tau Amyloid Fibrils Investigated by Solid-State Nuclear Magnetic Resonance.

The microtubule-associated protein tau aggregates into distinct neurofibrillary tangles in brains afflicted with multiple neurodegenerative diseases such as Alzheimer's disease and corticobasal degeneration (CBD). The mechanism of tau misfolding and aggregation is poorly understood. Determining the structure, dynamics, and water accessibility of tau filaments may provide insight into the pathway of tau misfolding.