Dynamics of Inter-Molecular Interactions Between Single Aβ42 Oligomeric and Aggregate Species by High-Speed Atomic Force Microscopy

Feng, Lei; Watanabe, Hiroki; Molino, Paul J.; Wallace, Gordon G.; Phung, Son Lam; Uchihashi, Takayuki; Higgins, Michael J.

doi:10.1016/j.jmb.2019.04.044

Cited by 19 publications

(28 citation statements)

References 74 publications

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“…A larger species had an area of 645 nm 2 with height of 7.7nm. These observations reproduce our previous findings using HS-AFM [5] (with all dimension values to within 5-10 %) and indicate the existence of oligomers in samples prepared from Aβ42 peptide solutions. The latter is not uncommon and likely due to either their rapid formation in solution [6], or incomplete disaggregation of the lypholized peptide [7].…”

Section: Ex-situ Method: Effect Of Ph On Aβ Peptide Solutionssupporting

confidence: 91%

“…When in close proximity, two individual species could come into contact to form a stable complex (Fig. 4), which we have previously observed and analyzed in-depth for interactions between the Aβ_EXISTING OLIGOMERS at pH 7 [5]. The binding between Aβ_NUCLEI is commonly observed (Fig.…”

Section: Single Molecule Aβ Interactions and Complex Formationmentioning

confidence: 71%

“…Namely, they have already formed in the sample solution prior to adsorption on the mica. These oligomers have previously been shown to be highly dynamic and capable of binding interactions to form stable complexes, particularly the larger aggregates[5,15]. Conversely, apart from a few suspected transient species on the mica, there is no clear indication of monomers despite being present at higher concentrations in the sample, indicating they are present in the bulk solution.After injecting with HCL in a pre-nucleation phase, the growth of existing oligomers proceeds linearly, revealing they are able to resume growth as a surface adsorbed species.…”

mentioning

confidence: 96%

“…Supplementary Figure 5. Movie sequence shown in Figure 3 with labelling of (A) individual existing oligomers (1,2,3) before injection and (B) new nuclei (4,5,6)…”

mentioning

confidence: 99%

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Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

Feng

Watanabe

Molino³

et al. 2020

Preprint

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Non-fibrillar oligomers formed via nucleation from amyloid beta (AB) peptides are currently implicated in the neurotoxicity of Alzheimers disease. Thus, shedding light on the molecular mechanisms underlying their formation is important for identifying targets for drug therapies. This is however an enduring challenge due to the inability to detect AB nucleation processes in the lag phase from bulk kinetic assays, while time-course analyses using a series of peptide solutions involve the discontinuous observation of dynamic nucleation processes and pathways. In this study, by adjusting the pH of AB42 peptide samples while simultaneously imaging with high-speed atomic force microscopy (HS-AFM), we show the in-situ, continuous visualization of dynamic AB42 nucleation at the molecular level. The process reveals a pH-induced saturation regime, enabling a critical monomer substrate concentration to initiate the birth of nucleation. A number of key nucleation phases are identified, including pre-nucleation, saturation regime (mass surface adsorption), nucleation and post-nucleation growth, eventually leading to the formation of predominately oligomer species. HS-AFM observations further reveal the distinct, molecular processes associated with each nucleation phase that constitute the path-dependent formation of different AB species, namely an intial monomer (diffuse-like) surface layer, followed by the emergence of nuclei and then subsequent formation and growth of new complexes and oligomers. In particular, the ability of individual nuclei to undergo surface diffusion and establish new complexes via binding interactions with other species encountered in the system was found to be a significant mechanism influencing the growth of oligomers. Herein, the study contributes to current AB nucleation theories by ascribing new molecular mechanisms. More generally, the knowledge gained from single molecule techniques can greatly assist in our current understanding of various biological processes of AB peptide such as nucleation, growth, aggregation and their related kinetic pathways.

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Section: Ex-situ Method: Effect Of Ph On Aβ Peptide Solutionssupporting

confidence: 91%

Section: Single Molecule Aβ Interactions and Complex Formationmentioning

confidence: 71%

mentioning

confidence: 96%

“…Supplementary Figure 5. Movie sequence shown in Figure 3 with labelling of (A) individual existing oligomers (1,2,3) before injection and (B) new nuclei (4,5,6)…”

mentioning

confidence: 99%

See 2 more Smart Citations

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

Feng

Watanabe

Molino³

et al. 2020

Preprint

Self Cite

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“…α-synuclein fibrils with different structures exhibited different toxicities [7] and caused different AFM was used to capture structural images and measure the nanomechanical properties of individual amyloid aggregates [85][86][87] in the ongoing heterologous aggregation processes of Aβ [20,[88][89][90][91][92][93][94][95][96][97][98], synuclein [90,[99][100][101][102][103][104][105][106], and amylin [107,108]. High-speed AFM (HS-AFM) enabled the kinetic measurement of the structural dynamics of biological molecular processes [79][80][81][82][83][84] including amyloid aggregation [93,[108][109][110][111][112][113][114][115][116]. Here, we show that HS-AFM links structural and dynamics studies, reviewing recent HS-AFM studies and including our findings for Aβ42 [93] and amylin [116], which is associated with ...…”

Section: Introductionmentioning

confidence: 99%

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Watanabe‐Nakayama

Sahoo

Ramamoorthy

et al. 2020

IJMS

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Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD.

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Remarked suppression of Aβ₄₂ protomer–protomer dissociation reaction elucidated by molecular dynamics simulation

Kurisaki

Tanaka

2022

Proteins

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Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half-century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril-like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid-β (Aβ 42 ). Seven different dimeric forms of oligomeric Aβ 42 fibril-like aggregate in aqueous solution, ranging from tetramer to decamer, were considered.We found additive effects of the size of these fibril-like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer-protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ 42 protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril-like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.

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Dynamics of Inter-Molecular Interactions Between Single Aβ42 Oligomeric and Aggregate Species by High-Speed Atomic Force Microscopy

Cited by 19 publications

References 74 publications

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Remarked suppression of Aβ₄₂ protomer–protomer dissociation reaction elucidated by molecular dynamics simulation

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Dynamics of Inter-Molecular Interactions Between Single Aβ42 Oligomeric and Aggregate Species by High-Speed Atomic Force Microscopy

Cited by 19 publications

References 74 publications

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

Key Nucleation Stages and Associated Molecular Determinants and Processes in pH-Induced Formation of Amyloid Beta Oligomers as Revealed by High-Speed AFM

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Remarked suppression of Aβ42 protomer–protomer dissociation reaction elucidated by molecular dynamics simulation

Contact Info

Product

Resources

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Remarked suppression of Aβ₄₂ protomer–protomer dissociation reaction elucidated by molecular dynamics simulation