Microchip Circulation Drastically Accelerates Amyloid Aggregation of 1–42 β-amyloid Peptide from <i>Felis catus</i>

Gospodarczyk, W.; Kozak, Maciej

doi:10.1021/acschemneuro.7b00285

Cited by 7 publications

(6 citation statements)

References 66 publications

(96 reference statements)

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“…It was shown that the addition of a depolymerization event (leading to the formation of a monomer and a (i–1) fibril)) to primary and secondary nucleation and elongation steps suffices to reproduce the time evolution of fibril concentrations at different shear rates . Similar kinetics behavior was reported for Aβ42 under fluid flows …”

Section: Resultsmentioning

confidence: 99%

“…112 Similar kinetics behaviour was reported for Aβ42 under fluid flows. 113 While shear-induced monomeric protein dynamics were explored by experimental 114,115 and computational [116][117][118][119][120] studies, and lipid systems were also investigated under shear flows, [121][122][123][124] we still lack an atomic description of Aβ aggregates under fluid flows in the bulk solution and at the surface of membranes. Yet is it known that flowing acting on the membrane surface showed desorption, diffusion and collision of Aβ-lipid aggregates forming larger plaque-like aggregates.…”

Section: Protein Self-assembly Near In Vivo Conditionsmentioning

confidence: 99%

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Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

2022

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Understanding the atomistic resolution changes during the self-assembly of amyloid peptides or proteins is important to develop compounds or conditions to alter the aggregation pathways and suppress the toxicity, and potentially aid in the development of drugs. However, the complexity of protein aggregation and the transient order/disorder of oligomers along pathways to fibril are very challenging. In this perspective, we discuss computational studies of amyloid polypeptides carried out under various conditions, including conditions closely mimicking in vivo, and point out the challenges in obtaining physiologically-relevant results, focusing mainly on the amyloid-beta Aβ peptides. 1.IntroductionAmyloid fibril with a cross β-structure and intermolecular H-bonds parallel to the long fibril axis is a hallmark of many sequences differing in amino acid length and composition involved in neurogenerative diseases. These involve Aβ and tau proteins in Alzheimer's disease (AD), α-synuclein in Parkinson disease, superoxide dismutase 1 (SOD1) protein in amyotrophic lateral sclerosis, transthyretin protein in cardiac and systemic amyloidosis, prion protein in prion disease, and human islet amyloid polypeptide (hIAPP) in type 2 diabetes, among others.Fragments of these proteins form fibrils as well, which represent ideal systems for computational studies. 1 In this perspective, we mainly focus on the Aβ peptides. Results and Discussion Protein self-assembly under quiescent solution conditionsThe aggregation kinetics of amyloid proteins in aqueous solution, as measured by Thioflavin T (ThT) fluorescence assays, displays a sigmoidal curve with a lag-phase where monomers undergo conformational conversion and self-assemble into oligomers until the growth phase where the fibril elongates. This is followed by the saturation phase where the system is in equilibrium between fibrils and a low concentration of monomers. Aggregation is described by microscopic events involving primary nucleation, elongation and dissociation of a fibril by one monomer, and secondary (fibril fragmentation and fibril surface-catalyzed) nucleation. The rates of the different microscopic processes are obtained by fitting the experimental aggregation kinetic curves using multiple initial monomer concentrations. It was shown the aggregation kinetics is sensitive to variations in temperature, pH, protein concentration, ionic strength, and the presence of cofactors and preformed aggregates. 2 General questions probing amyloid fibril formation of short peptides adopting straight β-strands in the bulk solution were addressed by on-lattice models and Monte Carlo simulations. It was demonstrated that the energy difference between the monomeric native state and the fibril-prone (N*) state, and therefore the population of the ensemble of N* structures in the full spectrum of conformations, are the major determinants of the time for fibril formation. 3,4 Based on a cubic lattice that considers the formation of H-bonds and pairwise side chain interactions, 5 and replic...

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Section: Resultsmentioning

confidence: 99%

Section: Protein Self-assembly Near In Vivo Conditionsmentioning

confidence: 99%

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

2022

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“…Because the secondary structure of Aβ determines its cytotoxicity, changes in CSF flow due to aging or disorders , may increase toxicity by altering Aβ conformation. Furthermore, flow increases intermolecular alignment and decreases the energy barrier for nucleation, the molecular effects of which have been confirmed via the flow-dependent modulation of nucleation, fibril growth, and other intra- and intermolecular processes of Aβ and other biological macromolecules. − However, these studies examined Aβ in the absence of a cell membrane ( i.e. , stirring or shaking bath; Figure ) and did not evaluate the role of flowing condition on Aβ–lipid interactions and flow-triggered cytotoxicity.…”

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confidence: 99%

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Iida

Abe

Nochi

et al. 2021

J. Phys. Chem. Lett.

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Self-assembly of amyloid-β (Aβ) peptides in nonequilibrium, flowing conditions is associated with pathogenesis of Alzheimer’s disease. We examined the role of biologically relevant, nonequilibrium, flowing conditions in the desorption, diffusion, and integration of Aβ-lipid assemblies at the membrane surface using a microchannel connected with microsyringes. A 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayer was formed on a glass substrate and incubated in Aβ solution under either a quiescent condition (no flow) or flowing condition for 24 h. Although dot-like aggregates (<1 μm) comprising Aβ fibrils formed on the DMPC membrane under the quiescent condition, larger plaque-like aggregates formed under the flowing condition, suggesting that nonequilibrium continuous flow governs the cytotoxicity of Aβ species. We propose that Aβ adsorption on the membrane surface involves spontaneous desorption of Aβ-lipid to form self-assembling aggregates, with this accelerated by surface shear forces. These findings suggest that nonequilibrium, flowing conditions influence inter/intra-molecular Aβ-fibril formation to trigger formation of amyloid plaques.

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“…Mild shearing of Aβ-containing solutions has been shown to be sufficient to initiate fibril formation despite the very low total amount of energy and rate of energy input, which is reported to be less than that needed for the breakage of one hydrogen bond per molecule [ 22 ]. There is a recent report that micro-fluid flow of Aβ, modeling blood flow through very narrow flow paths, induced Aβ aggregation [ 32 ]. A critical paper reports that very gentle shear induces spectral changes that indicate subtle conformational changes in many different types of proteins [ 25 ], including Aβ (L. Ashton, private communication).…”

Section: In Vivo Shearmentioning

confidence: 99%

Shear-Induced Amyloid Formation in the Brain: III. The Roles of Shear Energy and Seeding in a Proposed Shear Model

Trumbore

2018

JAD

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If cerebrospinal and interstitial fluids move through very narrow brain flow channels, these restrictive surroundings generate varying levels of fluid shear and different shear rates, and dissolved amyloid monomers absorb different shear energies. It is proposed that dissolved amyloid-β protein (Aβ) and other amyloid monomers undergo shear-induced conformational changes that ultimately lead to amyloid monomer aggregation even at very low brain flow and shear rates. Soluble Aβ oligomers taken from diseased brains initiate in vivo amyloid formation in non-diseased brains. The brain environment is apparently responsible for this result. A mechanism involving extensional shear is proposed for the formation of a seed Aβ monomer molecule that ultimately promotes templated conformational change of other Aβ molecules. Under non-quiescent, non-equilibrium conditions, gentle extensional shear within the brain parenchyma, and perhaps even during laboratory preparation of Aβ samples, may be sufficient to cause subtle conformational changes in these monomers. These result from brain processes that significantly lower the high activation energy predicted for the quiescent Aβ dimerization process. It is further suggested that changes in brain location and changes brought about by aging expose Aβ molecules to different shear rates, total shear, and types of shear, resulting in different conformational changes in these molecules. The consequences of such changes caused by variable shear energy are proposed to underlie formation of amyloid strains causing different amyloid diseases. Amyloid researchers are urged to undertake studies with amyloids, anti-amyloid drugs, and antibodies while all of these are under shear conditions similar to those in the brain.

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Microchip Circulation Drastically Accelerates Amyloid Aggregation of 1–42 β-amyloid Peptide from Felis catus

Cited by 7 publications

References 66 publications

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

Self-Assembly of Amyloid-Beta (Aβ) Peptides from Solution to Near In Vivo Conditions

Promoted Aggregation of Aβ on Lipid Bilayers in an Open Flowing System

Shear-Induced Amyloid Formation in the Brain: III. The Roles of Shear Energy and Seeding in a Proposed Shear Model

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