Competitive homo- and hetero- self-assembly of amyloid-β 1–42 and 1–40 in the early stage of fibrillation

Heo, Chae Eun; Choi, Tae Su; Kim, Hugh I.

doi:10.1016/j.ijms.2018.02.002

Cited by 11 publications

(16 citation statements)

References 53 publications

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“…The implication is that cross-interaction might occur more drastically for the formation of small, soluble rather than large, insoluble aggregates, as is the case with coassembly of two different Aβ isoforms. 80 Effects of αS on Aβ aggregation are summarized in Figure 5.…”

Section: ■ Discussionmentioning

confidence: 99%

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization

et al. 2019

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Aggregations of β-amyloid (Aβ) and α-synuclein (αS) into oligomeric and fibrillar assemblies are the pathological hallmarks of Alzheimer's and Parkinson's diseases, respectively. Although Aβ and αS affect different regions of the brain and are separated at the cellular level, there is evidence of their eventual interaction in the pathology of both disorders. Characterization of interactions of Aβ and αS at various stages of their aggregation pathways could reveal mechanisms and therapeutic targets for the prevention and cure of these neurodegenerative diseases. In this study, we comprehensively examined the interactions and their molecular manifestations using an array of characterization tools. We show for the first time that αS monomers and oligomers, but not αS fibrils, inhibit Aβ fibrillization while promoting oligomerization of Aβ monomers and stabilizing preformed Aβ oligomers via co-assembly, as judged by Thioflavin T fluorescence, transmission electron microscopy and SDS-and native-PAGE with fluorescently labeled peptides/proteins. In contrast, soluble Aβ species, such as monomers and oligomers, aggregate into fibrils, when incubated alone under the otherwise same condition. Our study provides evidence that the interactions with αS soluble species, responsible for the effects, are mediated primarily by the Cterminus of Aβ, when judged by competitive immunoassays using antibodies recognizing various fragments of Aβ. We also show that the C-terminus of Aβ is a primary site for its interaction with αS fibrils. Collectively, these data demonstrate aggregation state-specific interactions between αS and Aβ, and offer insight into a molecular basis of synergistic biological effects between the two polypeptides.

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Section: ■ Discussionmentioning

confidence: 99%

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization

et al. 2019

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“…2NAO is a 6-mer, accordingly allowing for DB 6-mer and MB 3-mer. Experience has shown that CCS values computed straight from X-Ray, NMR or cryo-EM structures are usually not identical to experimental CCS as received from ESI gas phase ions ( Heo et al, 2018 ). We took potential alterations of the protein structures in the gas phase such as charge driven distortion or compaction due to self-solvation during the ESI process into account by performing vacuum MD simulation using Gromacs 5.0.7 ( Berendsen et al, 1995 ; Pronk et al, 2013 ; Van Der Spoel et al, 2005 ).…”

Section: Methodsmentioning

confidence: 99%

Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer’s disease related oligomers

Lieblein

Zangl

Martin

et al. 2020

eLife

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The formation of oligomers of the amyloid-β peptide plays a key role in the onset of Alzheimer's disease. We describe herein the investigation of disease-relevant small amyloid-β oligomers by mass spectrometry and ion mobility spectrometry, revealing functionally relevant structural attributes. In particular we can show that amyloid-β oligomers develop in two distinct arrangements leading to either neurotoxic oligomers and fibrils or non-toxic amorphous aggregates. Comprehending the key-attributes responsible for those pathways on a molecular level is a pre-requisite to specifically target the peptide's tertiary structure with the aim to promote the emergence of non-toxic aggregates. Here we show for two fibril inhibiting ligands, an ionic molecular tweezer and a hydrophobic peptide that despite their different interaction mechanisms, the suppression of the fibril pathway can be deduced from the disappearance of the corresponding structure of the first amyloid-β oligomers.

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“…ThT concentration was determined using UV–vis spectroscopy (ε 412 = 36 000 M –1 cm –1 ). For ThT fluorescence assay of K18, hIAPP, Aβ40, and Aβ42, 110 μL of 50 μM ThT solution was mixed with 40 μL aliquots of protein samples at each time point . For ThT fluorescence assay of αSyn, 146 μL of 50 μM ThT solution was mixed with 4 μL aliquots of αSyn samples.…”

Section: Methodsmentioning

confidence: 99%

“…For ThT fluorescence assay of K18, hIAPP, Aβ40, and Aβ42, 110 μL of 50 μM ThT solution was mixed with 40 μL aliquots of protein samples at each time point. 41 For ThT fluorescence assay of αSyn, 146 μL of 50 μM ThT solution was mixed with 4 μL aliquots of αSyn samples. The change in the fluorescence intensity was measured using a FluoroMate FS-2 (Scinco, Seoul, Korea) with the excitation wavelength at 446 nm and emission wavelength at 490 nm.…”

Section: ■ Conclusionmentioning

confidence: 99%

ATP Kinetically Modulates Pathogenic Tau Fibrillations

Heo

Han

Lim

et al. 2020

ACS Chem. Neurosci.

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Advanced understanding of Alzheimer's disease (AD) and several tauopathies over the past decades indicates the pathological importance of tau aggregation in these diseases. Herein, we demonstrated that adenosine triphosphate (ATP), a highly charged anionic molecule abundant in the cytosol of cells, catalyses tau fibrillation via supramolecular complexation with basic residues of tau. Our results showed that ATP attracts multiple lysine residues of four-repeat domain of tau (K18), thereby immediately forming dimers which convert to nuclei to accelerate fibril elongation. However, ATP was not directly incorporated in the K18 fibrils suggesting a catalytic role of ATP in K18 fibrillation. We also characterized the correlation between ATP dyshomeostasis and tau aggregation in the cellular environment. Our multiple biophysical approaches, including native mass spectrometry (MS), small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulation, provided insights into the molecular-level influence of ATP on the structural change and fibrillation of tau. File list (2) download file view on ChemRxiv 200314_TauATP_Preprint.pdf (1.62 MiB) download file view on ChemRxiv 200314_SI_TauATP_Preprint.pdf (1.47 MiB)

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Competitive homo- and hetero- self-assembly of amyloid-β 1–42 and 1–40 in the early stage of fibrillation

Cited by 11 publications

References 53 publications

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization

Interactions between Soluble Species of β-Amyloid and α-Synuclein Promote Oligomerization while Inhibiting Fibrillization

Structural rearrangement of amyloid-β upon inhibitor binding suppresses formation of Alzheimer’s disease related oligomers

ATP Kinetically Modulates Pathogenic Tau Fibrillations

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