Unseeded Aβ(1-40) amyloid fibrils
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ABSTRACT:
SUBMITTER: Matthias Schmidt
PROVIDER: EMPIAR-11595 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description: Not available
| S-EPMC10905702 | biostudies-literature
Project description:Amyloid fibrils are highly ordered protein aggregates that are associated with several pathological processes, including prion propagation and Alzheimer's disease. A key issue in amyloid science is the need to understand the mechanical properties of amyloid fibrils and fibers to quantify biomechanical interactions with surrounding tissues, and to identify mechanobiological mechanisms associated with changes of material properties as amyloid fibrils grow from nanoscale to microscale structures. Here we report a series of computational studies in which atomistic simulation, elastic network modeling, and finite element simulation are utilized to elucidate the mechanical properties of Alzheimer's Abeta(1-40) amyloid fibrils as a function of the length of the protein filament for both twofold and threefold symmetric amyloid fibrils. We calculate the elastic constants associated with torsional, bending, and tensile deformation as a function of the size of the amyloid fibril, covering fibril lengths ranging from nanometers to micrometers. The resulting Young's moduli are found to be consistent with available experimental measurements obtained from long amyloid fibrils, and predicted to be in the range of 20-31 GPa. Our results show that Abeta(1-40) amyloid fibrils feature a remarkable structural stability and mechanical rigidity for fibrils longer than approximately 100 nm. However, local instabilities that emerge at the ends of short fibrils (on the order of tens of nanometers) reduce their stability and contribute to their disassociation under extreme mechanical or chemical conditions, suggesting that longer amyloid fibrils are more stable. Moreover, we find that amyloids with lengths shorter than the periodicity of their helical pitch, typically between 90 and 130 nm, feature significant size effects of their bending stiffness due the anisotropy in the fibril's cross section. At even smaller lengths (50 nm), shear effects dominate lateral deformation of amyloid fibrils, suggesting that simple Euler-Bernoulli beam models fail to describe the mechanics of amyloid fibrils appropriately. Our studies reveal the importance of size effects in elucidating the mechanical properties of amyloid fibrils. This issue is of great importance for comparing experimental and simulation results, and gaining a general understanding of the biological mechanisms underlying the growth of ectopic amyloid materials.
| S-EPMC2872369 | biostudies-literature
Project description:Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disease characterized by the extracellular deposition of amyloid plaques. Investigation into the composition of these plaques revealed a high amount of amyloid-β (Aβ) fibrils and a high concentration of lipids, suggesting that fibril-lipid interactions may also be relevant for the pathogenesis of AD. Therefore, we grew Aβ40 fibrils in the presence of lipid vesicles and determined their structure by cryo-electron microscopy (cryo-EM) to high resolution. The fold of the major polymorph is similar to the structure of brain-seeded fibrils reported previously. The majority of the lipids are bound to the fibrils, as we show by cryo-EM and NMR spectroscopy. This apparent lipid extraction from vesicles observed here in vitro provides structural insights into potentially disease-relevant fibril-lipid interactions.
| S-EPMC10864299 | biostudies-literature
Project description:Low-lying excited states that correspond to rare conformations or transiently bound species have been hypothesized to play an important role for amyloid nucleation. Despite their hypothesized importance in amyloid formation, transiently occupied states have proved difficult to detect directly. To experimentally characterize these invisible states, we performed a series of Carr-Purcell-Meiboom-Gill (CPMG)-based relaxation dispersion NMR experiments for the amyloidogenic Aβ(1-40) peptide implicated in Alzheimer's disease. Significant relaxation dispersion of the resonances corresponding to the side-chain amides of Q15 and N27 was detected before the onset of aggregation. The resonances corresponding to the peptide backbone did not show detectable relaxation dispersion, suggesting an exchange rate that is not within the practical limit of detection. This finding is consistent with the proposed "dock and lock" mechanism based on molecular dynamics simulations in which the Aβ(1-40) monomer transiently binds to the Aβ(1-40) oligomer by non-native contacts with the side chains before being incorporated into the fiber through native contacts with the peptide backbone.
| S-EPMC3535185 | biostudies-literature
Project description:Understanding the structural mechanism by which proteins and peptides aggregate is crucial, given the role of fibrillar aggregates in debilitating amyloid diseases and bioinspired materials. Yet, this is a major challenge as the assembly involves multiple heterogeneous and transient intermediates. Here, we analyze the co-aggregation of Aβ40 and Aβ16-22, two widely studied peptide fragments of Aβ42 implicated in Alzheimer's disease. We demonstrate that Aβ16-22 increases the aggregation rate of Aβ40 through a surface-catalyzed secondary nucleation mechanism. Discontinuous molecular dynamics simulations allowed aggregation to be tracked from the initial random coil monomer to the catalysis of nucleation on the fibril surface. Together, the results provide insight into how dynamic interactions between Aβ40 monomers/oligomers on the surface of preformed Aβ16-22 fibrils nucleate Aβ40 amyloid assembly. This new understanding may facilitate development of surfaces designed to enhance or suppress secondary nucleation and hence to control the rates and products of fibril assembly.
| S-EPMC6588359 | biostudies-literature
Project description:The formation of Aβ amyloid fibrils is a neuropathological hallmark of Alzheimer's disease and cerebral amyloid angiopathy. However, the structure of Aβ amyloid fibrils from brain tissue is poorly understood. Here we report the purification of Aβ amyloid fibrils from meningeal Alzheimer's brain tissue and their structural analysis with cryo-electron microscopy. We show that these fibrils are polymorphic but consist of similarly structured protofilaments. Brain derived Aβ amyloid fibrils are right-hand twisted and their peptide fold differs sharply from previously analyzed Aβ fibrils that were formed in vitro. These data underscore the importance to use patient-derived amyloid fibrils when investigating the structural basis of the disease.
| S-EPMC6820800 | biostudies-other
Project description:Fibrillation of differently modified amyloid β peptides and deposition as senile plaques are hallmarks of Alzheimer's disease. N-terminally truncated variants, where the glutamate residue 3 is converted into cyclic pyroglutamate (pGlu), form particularly toxic aggregates. We compare the molecular structure and dynamics of fibrils grown from wildtype Aβ(1-40) and pGlu3-Aβ(3-40) on the single amino acid level. Thioflavin T fluorescence, electron microscopy, and X-ray diffraction reveal the general morphology of the amyloid fibrils. We found good agreement between the (13)C and (15)N NMR chemical shifts indicative for a similar secondary structure of both fibrils. A well-known interresidual contact between the two β-strands of the Aβ fibrils could be confirmed by the detection of interresidual cross peaks in a (13)C-(13)C NMR correlation spectrum between the side chains of Phe 19 and Leu 34. Small differences in the molecular dynamics of residues in the proximity to the pyroglutamyl-modified N-terminus were observed as measured by DIPSHIFT order parameter experiments.
| S-EPMC5030707 | biostudies-literature
Project description:ObjectiveTo explore whether the plasma total β-amyloid (Aβ) Aβ42/Aβ40 ratio is a reliable predictor of the amyloid-PET status by exploring the association between these 2 variables in a subset of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging cohort.MethodsTaking plasma samples at 3 separate time points, month 18 (n = 176), month 36 (n = 169), and month 54 (n = 135), we assessed the total Aβ42/Aβ40 ratio in plasma (TP42/40) with regard to neocortical Aβ burden via PET standardized uptake value ratio (SUVR) and investigated both association with Aβ-PET status and correlation (and agreement) with SUVR.ResultsThe TP42/40 plasma ratio was significantly reduced in amyloid-PET-positive participants at all time points (p < 0.0001). Adjusting for covariates age, gender, APOE ε4 allele status, and clinical classification clearly affects the significance, with p values reduced and only comparisons at 54 months retaining significance (p = 0.006). Correlations with SUVR were similar across each time point, with Spearman ρ reaching -0.64 (p < 0.0001). Area under the curve values were highly reproducible over time points, with values ranging from 0.880 at 36 months to 0.913 at 54 months. In assessments of the healthy control group only, the same relationships were found.ConclusionsThe current study demonstrates reproducibility of the plasma assay to discriminate between amyloid-PET positive and negative over 3 time points, which can help to substantially reducing the screening rate of failure for clinical trials targeting preclinical or prodromal disease.Classification of evidenceThis study provides Class II evidence that plasma total Aβ42/Aβ40 ratio is associated with neocortical amyloid burden as measured by PET SUVR.
| S-EPMC7251518 | biostudies-literature
Project description:Detailed structural studies of amyloid fibrils can elucidate the way in which their constituent polypeptides are folded and self-assemble, and exert their neurotoxic effects in Alzheimer's disease (AD). We have previously reported that when aqueous solutions of the N-terminal hydrophilic peptides of AD beta-amyloid (A beta) are gradually dried in a 2-Tesla magnetic field, they form highly oriented fibrils that are well suited to x-ray fiber diffraction. The longer, more physiologically relevant sequences such as A beta(1-40) have not been amenable to such analysis, owing to their strong propensity to polymerize and aggregate before orientation is achieved. In seeking an efficient and inexpensive method for rapid screening of conditions that could lead to improved orientation of fibrils assembled from the longer peptides, we report here that the birefringence of a small drop of peptide solution can supply information related to the cooperative packing of amyloid fibers and their capacity for magnetic orientation. The samples were examined by electron microscopy (negative and positive staining) and x-ray diffraction. Negative staining showed a mixture of straight and twisted fibers. The average width of both types was approximately 70 A, and the helical pitch of the latter was approximately 460 A. Cross sections of plastic-embedded samples showed a approximately 60-A-wide tubular structure. X-ray diffraction from these samples indicated a cross-beta fiber pattern, characterized by a strong meridional reflection at 4.74 A and a broad equatorial reflection at 8.9 A. Modeling studies suggested that tilted arrays of beta-strands constitute tubular, 30-A-diameter protofilaments, and that three to five of these protofilaments constitute the A beta fiber. This type of structure--a multimeric array of protofilaments organized as a tubular fibril--resembles that formed by the shorter A beta fragments (e.g., A beta(6-25), A beta(11-25), A beta(1-28)), suggesting a common structural motif in AD amyloid fibril organization.
| S-EPMC1299406 | biostudies-other