Detailed Mechanism of Rapid Amyloid Fibril Self-Assembly Due to Surface Diffusion

AbstractA key hallmark of Alzheimer’s disease is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein, the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its assembly enhancing properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

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Quantification of amyloid fibril polymorphism by nano-morphometry reveals the individuality of filament assembly

Communications Chemistry ◽

10.1038/s42004-020-00372-3 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Liam D. Aubrey ◽

Ben J. F. Blakeman ◽

Liisa Lutter ◽

Christopher J. Serpell ◽

Mick F. Tuite ◽

...

Keyword(s):

Self Assembly ◽

Amyloid Fibrils ◽

Amyloid Fibril ◽

Biological Function ◽

Structural Basis ◽

Distance Curve ◽

Filament Assembly ◽

Sample Heterogeneity ◽

Structural Insights ◽

Polymorphic Nature

Abstract Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-distance curve-based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.

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Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421204112 ◽

2015 ◽

Vol 112 (16) ◽

pp. E1994-E2003 ◽

Cited By ~ 228

Author(s):

Serene W. Chen ◽

Srdja Drakulic ◽

Emma Deas ◽

Myriam Ouberai ◽

Francesco A. Aprile ◽

...

Keyword(s):

Structural Characterization ◽

Self Assembly ◽

Protein Misfolding ◽

Amyloid Fibril ◽

Amyloid Formation ◽

Image Reconstruction Techniques ◽

Cryo Electron Microscopy ◽

Amyloid Oligomers ◽

Β Sheet

We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.

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Algorithms for Parameterizing Network Hamiltonians for Simulations of Amyloid Fibril Self-assembly

Biophysical Journal ◽

10.1016/j.bpj.2019.11.1731 ◽

2020 ◽

Vol 118 (3) ◽

pp. 306a

Author(s):

Gianmarc Grazioli ◽

Yue Yu ◽

Megha H. Unhelkar ◽

Rachel W. Martin ◽

Carter T. Butts

Keyword(s):

Self Assembly ◽

Amyloid Fibril

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Origin of metastable oligomers and their effects on amyloid fibril self-assembly

Chemical Science ◽

10.1039/c8sc01479e ◽

2018 ◽

Vol 9 (27) ◽

pp. 5937-5948 ◽

Cited By ~ 25

Author(s):

Filip Hasecke ◽

Tatiana Miti ◽

Carlos Perez ◽

Jeremy Barton ◽

Daniel Schölzel ◽

...

Keyword(s):

Self Assembly ◽

Amyloid Fibril ◽

Fibril Formation ◽

Simultaneous Analysis ◽

Inhibitory Effects ◽

Amyloid Fibril Formation ◽

Assembly Kinetics

Simultaneous analysis of oligomer and fibril assembly kinetics reveals inhibitory effects of metastable oligomers on amyloid fibril formation.

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The Mechanisms for Nanoparticle Surface Diffusion and Chain Self-Assembly Determined from Real-Time Nanoscale Kinetics in Liquid

The Journal of Physical Chemistry C ◽

10.1021/acs.jpcc.5b07164 ◽

2015 ◽

Vol 119 (36) ◽

pp. 21261-21269 ◽

Cited By ~ 49

Author(s):

Taylor J. Woehl ◽

Tanya Prozorov

Keyword(s):

Real Time ◽

Surface Diffusion ◽

Self Assembly ◽

Nanoparticle Surface

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Self-assembly of two-dimensional DNA origami lattices using cation-controlled surface diffusion

Nature Communications ◽

10.1038/ncomms5889 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 91

Author(s):

Sungwook Woo ◽

Paul W. K. Rothemund

Keyword(s):

Surface Diffusion ◽

Self Assembly ◽

Dna Origami ◽

Two Dimensional

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Cell-derived hexameric β-amyloid: a novel insight into composition, self-assembly and nucleating properties

10.1101/2020.12.15.422916 ◽

2020 ◽

Author(s):

Devkee M Vadukul ◽

Céline Vrancx ◽

Pierre Burguet ◽

Sabrina Contino ◽

Nuria Suelves ◽

...

Keyword(s):

Self Assembly ◽

Critical Nucleus ◽

Amyloid Fibril ◽

Amyloid Β ◽

Aβ Peptide ◽

Amyloid A ◽

Amyloid Fibril Formation ◽

Secretase Activity ◽

Β Amyloid ◽

Insight Into

A key hallmark of Alzheimer's disease (AD) is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein (APP), the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its nucleating properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.

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Excitation-Induced Low Temperature Epitaxial Growth of Ge on Si(100)

MRS Proceedings ◽

10.1557/opl.2011.297 ◽

2011 ◽

Vol 1305 ◽

Author(s):

Ali Oguz Er ◽

Hani Elsayed-Ali

Keyword(s):

Epitaxial Growth ◽

Surface Diffusion ◽

Self Assembly ◽

Laser Energy ◽

High Energy ◽

Laser Wavelength ◽

Ex Situ ◽

Recovery Curves ◽

Excitation Laser ◽

Growth Changes

ABSTRACTThe effect of laser-induced electronic excitations on the self-assembly of Ge quantum dots (QD) on Si(100)-(2x1) grown by pulsed laser deposition is studied. The experiment was conducted in ultrahigh vacuum. A Q-switched Nd:YAG laser (wavelength λ = 1064 nm, 10 Hz repetition rate) was split into two beams; one used to ablate a Ge target while the other to electronically excite the substrate. In situ reflection high-energy electron diffraction (RHEED) and ex situ atomic force microscopy (AFM) were used to study the morphology of the grown QDs. The dependence of the QD morphology on substrate temperature and ablation and excitation laser energy density was studied. Electronic excitation is shown to affect the surface morphology. For Ge coverage of 22 monolayer, it was observed that the excitation laser reduces the epitaxial growth temperature to 250 °C, a temperature at which no epitaxy is possible without excitation. Applying the excitation laser to the substrate during the growth changes the QD morphology and island density and improves the size uniformity of QDs at 390 °C. Surface diffusion measurement calculated from RHEED recovery curves show that the excitation-laser increases the surface diffusion of the Ge atoms. A purely electronic mechanism of enhanced surface diffusion of the Ge adatoms is involved.

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