Seeded Aβ(1-40) amyloid fibril
Ontology highlight
ABSTRACT:
SUBMITTER: Matthias Schmidt
PROVIDER: EMPIAR-11596 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description: Not available
| EMPIAR-11595 | biostudies-other
Project description:Nanoscale fibrils formed by amyloid peptides have a polymorphic character, adopting several types of molecular structures in similar growth conditions. As shown by experimental (e.g., solid-state NMR) and computational studies, amyloid fibril polymorphism hinders both the structural characterization of Alzheimer's Aβ amyloid protofilaments and fibrils at a molecular level, as well as the possible applications (e.g., development of drugs or biomarkers) that rely on similar, controlled molecular arrangements of the Aβ peptides in amyloid fibril structures. We have explored the use of several contact potentials for the efficient identification of minimal sequence mutations that could enhance the stability of specific fibril structures while simultaneously destabilizing competing topologies, controlling thus the amount of structural polymorphism in a rational way. We found that different types of contact potentials, while having only partial accuracy on their own, lead to similar results regarding ranking the compatibility of wild-type (WT) and mutated amyloid sequences with different fibril morphologies. This approach allows exhaustive screening and assessment of possible mutations and the identification of minimal consensus mutations that could stabilize fibrils with the desired topology at the expense of other topology types, a prediction that is further validated using atomistic molecular dynamics with explicit water molecules. We apply this two-step multiscale (i.e., residue and atomistic-level) approach to predict and validate mutations that could bias either parallel or antiparallel packing in the core Alzheimer's Aβ9-40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of structural polymorphism in WT Aβ fibrils, our study could also lead to efficient tools for assisting future experimental approaches for amyloid fibril determination, and for the development of biomarkers or drugs aimed at interfering with the stability of amyloid fibrils, as well as for the future design of amyloid fibrils with a controlled (e.g., reduced) level of structural polymorphism.
| S-EPMC6472267 | biostudies-literature
Project description:We have developed the stochastic microscopic-order-macroscopic-disorder (MOMD) approach for elucidating dynamic structures in the solid-state from 2H NMR lineshapes. In MOMD, the probe experiences an effective/collective motional mode. The latter is described by a potential, u, which represents the local spatial-restrictions, a local-motional diffusion tensor, R, and key features of local geometry. Previously we applied MOMD to the well-structured core domain of the 3-fold-symmetric twisted polymorph of the Aβ40-amyloid fibril. Here, we apply it to the N-terminal domain of this fibril. We find that the dynamic structures of the two domains are largely similar but differ in the magnitude and complexity of the key physical parameters. This interpretation differs from previous multisimple-mode (MSM) interpretations of the same experimental data. MSM used for the two domains different combinations of simple motional modes taken to be independent. For the core domain, MOMD and MSM disagree on the character of the dynamic structure. For the N-terminal domain, they even disagree on whether this chain segment is structurally ordered (MOMD finds that it is), and whether it undergoes a phase transition at 260 K where bulklike water located in the fibril matrix freezes (MOMD finds that it does not). These are major differences associated with an important system. While the MOMD description is a physically sound one, there are drawbacks in the MSM descriptions. The results obtained in this study promote our understanding of the dynamic structure of protein aggregates. Thus, they contribute to the effort to pharmacologically control neurodegenerative disorders believed to be caused by such aggregates.
| S-EPMC8908910 | biostudies-literature
Project description:Aggregation of amyloid-β (Aβ) peptides in brain tissue leads to neurodegeneration in Alzheimer's disease (AD). Regardless of the kinetics or detailed mechanisms of Aβ aggregation, aggregation can only occur if Aβ concentrations exceed their local equilibrium solubility values. We propose that excess Aβ peptides can be removed from supersaturated solutions, including solutions in biological fluids, by the addition of hydrogels that are seeded with Aβ fibril fragments. Fibril growth within the hydrogels then sequesters excess peptides until equilibrium concentrations are reached. Experiments with 40- and 42-residue Aβ peptides (Aβ40 and Aβ42) in phosphate buffer at 24°C and in filtered fetal bovine serum at 37°C, using crosslinked polyacrylamide hydrogels, demonstrate the validity of this concept. Aβ sequestration in fibril-seeded hydrogels (or other porous media) may prove to be a useful technique in experiments with animal models of AD and may represent a possible approach to preventing or slowing the progression of AD in humans.
| S-EPMC6032349 | biostudies-literature
Project description:The long lag times and subsequent rapid growth of Alzheimer's Aβ42 fibrils can be explained by a secondary nucleation step, in which existing fibril surfaces are able to nucleate the formation of new fibrils via an autocatalytic process. The molecular mechanism of secondary nucleation, however, is still unknown. Here we investigate the first step, namely, adsorption of the Aβ42 peptide monomers onto the fibril surface. Using long all-atom molecular simulations and an enhanced sampling scheme, we are able to generate a diverse ensemble of binding events. The resulting thermodynamics of adsorption are consistent with experiment as well as with the requirements for effective autocatalysis determined from coarse-grained simulations. We identify the key interactions stabilizing the adsorbed state, which are predominantly polar in nature, and relate them to the effects of known disease-causing mutations.
| S-EPMC7507730 | biostudies-literature
Project description:Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1-40) and Aβ(1-42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1-42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer's disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1-42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15-42 forming a double-horseshoe-like cross-β-sheet entity with maximally buried hydrophobic side chains. Residues 1-14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.
| S-EPMC5003276 | biostudies-literature
Project description: Not available
| S-EPMC6355333 | biostudies-literature
Project description:The structure of the Aβ(11-42) amyloid available in PDB makes possible the molecular analysis of the specificity of amyloid formation. This molecule (PDB ID 2MVX) is the object of analysis. This work presents the outcome of in silico experiments involving various alternative conformations of the Aβ(11-42) sequence, providing clues as to the amylodogenecity of its constituent fragments. The reference structure (PDB) has been compared with folds generated using I-Tasser and Robetta-the strongest contenders in the CASP challenge. Additionally, a polypeptide which matches the Aβ(11-42) sequence has been subjected to folding simulations based on the fuzzy oil drop model, which favors the production of a monocentric hydrophobic core. Computer simulations yielded 15 distinct structural forma (five per software package), which, when compared to the experimentally determined structure, allow us to study the role of structural elements which cause an otherwise globular protein to transform into an amyloid. The unusual positions of hydrophilic residues disrupting the expected hydrophobic core and propagating linearly along the long axis of fibril is recognized as the seed for amyloidogenic transformation in this polypeptide. This paper discusses the structure of the Aβ(11-42) amyloid fibril, listed in PDB under ID 2MXU (fragment od Aβ(1-42) amyloid).
| S-EPMC6687686 | biostudies-literature
Project description:Studies by solid-state nuclear magnetic resonance (NMR) of amyloid fibrils prepared in vitro from synthetic 40-residue beta-amyloid (Abeta(1-40)) peptides have shown that the molecular structure of Abeta(1-40) fibrils is not uniquely determined by amino acid sequence. Instead, the fibril structure depends on the precise details of growth conditions. The molecular structures of beta-amyloid fibrils that develop in Alzheimer's disease (AD) are therefore uncertain. We demonstrate through thioflavin T fluorescence and electron microscopy that fibrils extracted from brain tissue of deceased AD patients can be used to seed the growth of synthetic Abeta(1-40) fibrils, allowing preparation of fibrils with isotopic labeling and in sufficient quantities for solid-state NMR and other measurements. Because amyloid structures propagate themselves in seeded growth, as shown in previous studies, the molecular structures of brain-seeded synthetic Abeta(1-40) fibrils most likely reflect structures that are present in AD brain. Solid-state (13)C NMR spectra of fibril samples seeded with brain material from two AD patients were found to be nearly identical, indicating the same molecular structures. Spectra of an unseeded control sample indicate greater structural heterogeneity. (13)C chemical shifts and other NMR data indicate that the predominant molecular structure in brain-seeded fibrils differs from the structures of purely synthetic Abeta(1-40) fibrils that have been characterized in detail previously. These results demonstrate a new approach to detailed structural characterization of amyloid fibrils that develop in human tissue, and to investigations of possible correlations between fibril structure and the degree of cognitive impairment and neurodegeneration in AD.
| S-EPMC2678625 | biostudies-literature
Project description:Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.
| S-EPMC4476499 | biostudies-literature