Unseeded Aβ(1-40) amyloid fibrils
Ontology highlight
ABSTRACT:
SUBMITTER: Matthias Schmidt
PROVIDER: EMPIAR-11595 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:The p3 peptides, Aβ17-40/42, are a common alternative cleavage product of the amyloid precursor protein, and are found in diffuse amyloid deposits of Alzheimer's and Down Syndrome brains. The p3 peptides have been mis-named 'non-amyloidogenic'. Here we show p340/42 peptides rapidly form amyloid fibrils, with kinetics dominated by secondary nucleation. Importantly, cross-seeding experiments, with full-length Aβ induces a strong nucleation between p3 and Aβ peptides. The cross-seeding interaction is highly specific, and occurs only when the C-terminal residues are matched. We have imaged membrane interactions with p3, and monitored Ca2+ influx and cell viability with p3 peptide. Together this data suggests the N-terminal residues influence, but are not essential for, membrane disruption. Single particle analysis of TEM images indicates p3 peptides can form ring-like annular oligomers. Patch-clamp electrophysiology, shows p342 oligomers are capable of forming large ion-channels across cellular membranes. A role for p3 peptides in disease pathology should be considered as p3 peptides are cytotoxic and cross-seed Aβ fibril formation in vitro.
| S-EPMC11868391 | biostudies-literature
Project description:The COVID-19 infection has been more problematic for individuals with certain health predispositions. Coronaviruses could also interfere with neural diseases if the viruses succeed in entering the brain. Therefore, it might be of principal interest to examine a possible coupling of coronaviruses and amyloid fibrils. Here, molecular dynamics simulations were used to investigate direct coupling of SARS-CoV-2 and Aβ fibrils, which play a central role in neural diseases. The simulations revealed several stable binding configurations and their dynamics of Aβ42 fibrils attached to spike proteins of the Omicron and Alpha variants of SARS-CoV-2.
| S-EPMC10905702 | biostudies-literature
Project description:Recent studies indicate that the pathogenesis of Alzheimer disease may be related to the interaction between prion protein (PrP) and certain oligomeric species of Aβ peptide. However, the mechanism of this interaction remains unclear and controversial. Here we provide direct experimental evidence that, in addition to previously demonstrated binding to Aβ oligomers, PrP also interacts with mature Aβ fibrils. However, contrary to the recent claim that PrP causes fragmentation of Aβ fibrils into oligomeric species, no evidence for such a disassembly could be detected in the present study. In contrast, our data indicate that the addition of PrP to preformed Aβ fibrils results in a lateral association of individual fibrils into larger bundles. These findings have potentially important implications for understanding the mechanism by which PrP might impact Aβ toxicity as well as for the emerging efforts to use PrP-derived compounds as inhibitors of Aβ-induced neurodegeneration.
| S-EPMC4030797 | biostudies-literature
Project description:Amyloid β (Aβ) is a hallmark protein of Alzheimer's disease. One physiologically important Aβ variant is formed by initial N-terminal truncation at a glutamic acid position (either E3 or E11), which is subsequently cyclized to a pyroglutamate (either pE3 or pE11). Both forms have been found in high concentrations in the core of amyloid plaques and are likely of high importance in the pathology of Alzheimer's disease. However, the molecular structure of the fibrils of these variants is not entirely clear. Solid-state NMR spectroscopy studies have reported a molecular contact between Gly25 and Ile31, which would disagree with the conventional hairpin model of wildtype (WT-)Aβ1-40 fibrils, most often described in the literature. We investigated the conformation of the monomeric unit of pE3-Aβ3-40 and pE11-Aβ11-40 (and for comparison also wildtype (WT)-Aβ1-40) fibrils to find out whether the hairpin or a newly suggested extended structure dominates the structure of the Aβ monomers in these fibrils. To this end, solid-state NMR spectroscopy was applied probing the inter-residual contacts between Phe19/Leu34, Ala21/Leu34, and especially Gly25/Ile31 using suitable isotopic labeling schemes. In the second part, the flexible turn of the Aβ40 peptides was replaced by a (3-(3-aminomethyl)phenylazo)phenylacetic acid (AMPP)-based photoswitch, which can predefine the peptide conformation to either an extended (trans) or hairpin (cis) conformation. This enables simultaneous spectroscopic assessment of the conformation of the AMPP-photoswitch, allowing in situ structural investigations during fibrillation in contrast to structural techniques such as NMR spectroscopy or cryo-EM, which can only be applied to stable conformers. Both methods confirm an extended structure for the peptidic monomers in fibrils of all investigated Aβ variants. Especially the Gly25/Ile31 contact is a decisive indicator for the extended structure along with the characteristic absorption spectra of trans-AMPP-Aβ.
| S-EPMC10895672 | 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:Using implicit solvent model and replica exchange molecular dynamics, we examine the propensity of a nonsteroidal anti-inflammatory drug, naproxen, to interfere with Aβ fibril growth. We also compare the antiaggregation propensity of naproxen with that of ibuprofen. Naproxen's antiaggregation effect is influenced by two factors. Similar to ibuprofen, naproxen destabilizes binding of incoming Aβ peptides to the fibril due to direct competition between the ligands and the peptides for the same binding location on the fibril surface (the edge). However, in contrast to ibuprofen, naproxen binding also alters the conformational ensemble of Aβ monomers by promoting β-structure. The second factor weakens naproxen's antiaggregation effect. These findings appear to explain the experimental observations, in which naproxen binds to the Aβ fibril with higher affinity than ibuprofen, yet produces weaker antiaggregation action.
| S-EPMC3034367 | 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-literature
Project description:The molecular chaperone αB-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with Aβ amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with Aβ fibrils in vitro. We find that αB-crystallin binds to wild-type Aβ(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of Aβ(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of αB-crystallin on the seeded growth of Aβ fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of αB-crystallin to seed fibrils strongly inhibits their elongation. Because the lag phase in sigmoidal fibril assembly kinetics is dominated by elongation and fragmentation rates, the chaperone mechanism identified here represents a highly effective means to inhibit fibril proliferation. Together with previous observations of αB-crystallin interaction with α-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation.
| S-EPMC3183811 | biostudies-literature