ATP Impedes the Inhibitory Effect of Hsp90 on Aβ40 Fibrillation

Wang, Hongzhi; Lallemang, Max; Hermann, B. A.; Wallin, Cecilia; Loch, R.A.; Blanc, Alain; Balzer, Bizan N.; Hugel, Thorsten; Luo, Jinghui

doi:10.1016/j.jmb.2020.11.016

Cited by 14 publications

(13 citation statements)

References 72 publications

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“…Such inhibition of secondary nucleation is linked to a decrease in toxicity, as the amount of toxic prefibrillar aggregates is greatly decreased ( Flagmeier et al, 2020 ). The inhibition of Aβ aggregation in the presence of NCAM-PrP is similar to the impact of chaperone proteins on Aβ aggregation ( Cohen et al, 2015 ; Leppert et al., 2019 ; Chen et al, 2017 ; Scheidt et al, 2019 ; Wang et al, 2020 ). The chaperone-functional BRICHOS domain, consisting of about 100 amino acids, is found in several proteins related to amyloid formation and is an example of a chaperone which inhibits secondary nucleation ( Leppert et al., 2019 ; Chen et al, 2017 ).…”

Section: Discussionmentioning

confidence: 59%

The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

et al. 2021

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Summary Substantial research efforts have gone into elucidating the role of protein misfolding and self-assembly in the onset and progression of Alzheimer’s disease (AD). Aggregation of the Amyloid-β (Aβ) peptide into insoluble fibrils is closely associated with AD. Here, we use biophysical techniques to study a peptide-based approach to target Aβ amyloid aggregation. A peptide construct, NCAM-PrP, consists of a largely hydrophobic signal sequence linked to a positively charged hexapeptide. The NCAM-PrP peptide inhibits Aβ amyloid formation by forming aggregates which are unavailable for further amyloid aggregation. In a membrane-mimetic environment, Aβ and NCAM-PrP form specific heterooligomeric complexes, which are of lower aggregation states compared to Aβ homooligomers. The Aβ:NCAM-PrP interaction appears to take place on different aggregation states depending on the absence or presence of a membrane-mimicking environment. These insights can be useful for the development of potential future therapeutic strategies targeting Aβ at several aggregation states.

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Section: Discussionmentioning

confidence: 59%

The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

et al. 2021

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“…As a p38 inhibitor had no measurable effect on the small NELF cluster, the response to it provides another means of distinguishing between small and large clusters. Future experiments of the type we have presented will reveal if these transient small clusters are also regulated by chaperones, which have already been shown to modulate size distributions of self-associating proteins [54], even in an ATP-dependent manner [55].…”

Section: Discussionmentioning

confidence: 99%

Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation

Kim

Ulferts

Aprile-Garcia

et al. 2022

Preprint

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The formation of biomolecular condensates underpins many cellular processes; however, our current understanding of condensate formation within cells is largely based on observing the final near-equilibrium condensate state. It is less clear how proteins behave before condensates form or at concentrations at which condensation does not occur in cells. Here, we use a combination of fluorescence microscopy and photobleaching analysis to quantify phase separation of negative elongation factor (NELF) in living and stressed cells. We use the recently reported system of stress-induced condensation of NELF in human nuclei as a model to study the behaviour of proteins before condensation. We find that pre-condensate heterogeneous clusters both grow and shrink and are not freely diffusing. Unexpectedly, we also find such small dynamic clusters in unstressed cells in which condensates do not form. We provide a categorisation of small and large clusters based on their dynamics and their response to p38 kinase inhibition. Overall, our data are best explained as non-classical nucleation with a flat free-energy landscape for clusters of a range of sizes and an inhibition of condensation.

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“…Global fitting. To identify how pH and salt affect the microscopic rate processes of Aβ 40 aggregation, the averaged ThT data obtained in the absence of Zn 2+ ions were smoothed with the same method used for the smooth process of individual curves and fitted globally with an integrated rate law 25,26 in AmyloFit online software server 29 by using the method in our previous study 16 . Briefly, the secondary nucleation dominated model was selected, the data of Aβ 40 at pH 7.4 in the absence of NaCl was first fitted, obtaining a set of parameters, which were used as the initial guess values for the following fits.…”

Section: Methodsmentioning

confidence: 99%

“…Among these obtained parameters, the primary nucleation rate constant secondary nucleation rate constant , or the elongation rate constant was fitted freely while the other two rate constants were set as fixed initial values. For detailed definitions of these parameters and fitting procedure, please refer to the nature protocol 29 and our previous study 16 . The fitting results are shown in Figs.…”

Section: Methodsmentioning

confidence: 99%

“…The Aβ aggregation is highly influenced by the pH, which is facilitated during sample preparation where a high pH (app. pH 11) is used to solubilize the sample and to avoid aggregation before experiments are executed at physiological pH 16 . For the other extreme condition, a low pH down to 2 is used for formation of more homogenous samples of Aβ fibrils needed for structural analysis using cryo-EM 17 .…”

Section: Introductionmentioning

confidence: 99%

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Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation

Wang

Sternke-Hoffmann

et al. 2022

Commun Chem

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Amyloid-β (Aβ) peptide aggregation plays a central role in the progress of Alzheimer’s disease (AD), of which Aβ-deposited extracellular amyloid plaques are a major hallmark. The brain micro-environmental variation in AD patients, like local acidification, increased ionic strength, or changed metal ion levels, cooperatively modulates the aggregation of the Aβ peptides. Here, we investigate the multivariate effects of varied pH, ionic strength and Zn2+ on Aβ40 fibrillation kinetics. Our results reveal that Aβ fibrillation kinetics are strongly affected by pH and ionic strength suggesting the importance of electrostatic interactions in regulating Aβ40 fibrillation. More interestingly, the presence of Zn2+ ions can further alter or even reserve the role of pH and ionic strength on the amyloid fibril kinetics, suggesting the importance of amino acids like Histidine that can interact with Zn2+ ions. Both pH and ionic strength regulate the secondary nucleation processes, however regardless of pH and Zn2+ ions, ionic strength can also modulate the morphology of Aβ40 aggregates. These multivariate effects in bulk solution provide insights into the correlation of pH-, ionic strength- or Zn2+ ions changes with amyloid deposits in AD brain and will deepen our understanding of the molecular pathology in the local brain microenvironment.

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ATP Impedes the Inhibitory Effect of Hsp90 on Aβ40 Fibrillation

Cited by 14 publications

References 72 publications

The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation

Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation

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