Dynamics of oligomer populations formed during the aggregation of Alzheimer’s A<i>β</i>42 peptide

Michaels, Thomas C. T.; Šarić, Anđela; Curk, Samo; Bernfur, Katja; Arosio, Paolo; Meisl, Georg; Dear, Alexander J.; Cohen, Samuel I.; Vendruscolo, Michele; Dobson, Christopher M.; Linse, Sara; Knowles, Tuomas P. J.

doi:10.1101/2020.01.08.897488

Cited by 32 publications

(68 citation statements)

References 42 publications

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“…These assays showed that both the size and the surface properties of these oligomers are dramatically affected by DesBP. These results suggest that the presence of DesBP may affect the conversion step by which early disordered aggregates reorganise their structures to more stable ordered β-sheet structure 40,84,85 .…”

Section: Discussionmentioning

confidence: 91%

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

Ikenoue

Aprile

Sormanni

et al. 2020

Sci Rep

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Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

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Section: Discussionmentioning

confidence: 91%

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

Ikenoue

Aprile

Sormanni

et al. 2020

Sci Rep

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“…These results are in excellent agreement and demonstrate at the single aggregate scale the conversion step from an antiparallel -sheet conformation in oligomeric species to a parallel -sheet conformation in the fibrillar products of the aggregation kinetics. 39 In the case of the oligomers, their crosssectional diameter was below the size of a single protein molecule of apoferritin, which was only very recently achieved. Although we could reach this high sensitivity, the measurement of the spectra of the oligomers was at the limit of the experimental sensitivity leading to a higher experimental noise and a partial suppression of the amide band II.…”

Section: Infrared Nanospectroscopy Of Single A42 Oligomers and Fibrilsmentioning

confidence: 99%

Infrared Nanospectroscopy Reveals the Molecular Interaction Fingerprint of an Aggregation Inhibitor with Single Aβ42 Oligomers

Ruggeri

Habchi

Chia

et al. 2020

Preprint

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Very significant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer's and Parkinson's diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule level morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the interaction between single A42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, originally an anticancer drug capable recently shown to be able to inhibit A42 aggregation in animal models of Alzheimer's disease.Our results demonstrate that the carbonyl group of this compound interacts with A42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as powerful tool in structure-based drug discovery for protein misfolding diseases.Alzheimer's disease (AD) is characterised by memory loss and cognitive impairment. AD is the primary cause of dementia, which affects currently over 50 million people worldwide, a number expected to exceed 150 million by 2050. 1-3 The self-assembly of the 42-residue isoform of the amyloid- (A) peptide into intractable aggregates is considered to be at the core of the molecular pathways leading to AD. [3][4][5] It is therefore important to understand at the molecular level the aggregation process of A42 in order to develop effective therapeutic strategies that aim at inhibiting its self-assembly.Great efforts have been devoted in the last twenty years to understand the molecular basis of this devastating disorder and to develop small molecules that could interfere with the aggregation pathway of A42. 6-12 Indeed, disease-modifying small molecules represent c.a. one third of the registered trials, in which anti-A therapies dominate. 13 However, despite these efforts, no compound has entered the clinical use to date. 13,14 These repeated failures are in part related to an incomplete understanding of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and how they interfere with the pathways of aggregation. It is increasingly recognised that inhibiting A aggregation per se could have unexpected consequences on the toxicity, as it could not only decrease it, but also leave it unaffected, or even increase it. 15 This complexity is due to the non-linear nature of the aggregation network, in which neurotoxic small oligomeric intermediates [16][17][18][19][20] , can be formed in a variety of ways, some of which highly sensitive to small perturbation. Therefore, promising effective therapeutic strategies must be aimed at targeting precise species in a controlled inte...

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“…transient oligomers. 55 We describe the effect of inhibitors on aggregation using a master equation by introducing species for the monomer concentration, the number and mass concentrations of fibrils which are either active (“free”, subscript “f”) or deactivated due to the binding to inhibitor molecules (“bound”, subscript “b”). In our model, bound species are unable to participate in the aggregation process 1 .…”

Section: Aggregation Kinetics In the Presence Of An Inhibitormentioning

confidence: 99%

Thermodynamic and kinetic design principles for protein aggregation inhibitors

Michaels

Šarić

Meisl

et al. 2020

Preprint

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Understanding the mechanism of action of compounds capable of inhibiting protein aggregation is critical to the development of potential ther-1 apeutics against protein misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of protein aggregation inhibition which reveals the fundamental thermodynamic and kinetic signatures characterising effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimisation of protein aggregation inhibitors.The aggregation of peptides and proteins into amyloid fibrils is key in many phenomena ranging from the formation of functional machineries in biology to the production of novel nanomaterials. Recent interest in this process has come from the realisation that protein aggregation is intimately linked to a range of human conditions, from Alzheimer's disease to type II diabetes. 1-6 Inhibition of protein aggregation thus represents a major strategy for the development of effective pharmacological interventions against protein misfolding diseases. 7-24 Traditionally, inhibition strategies against protein aggregation have focussed either on blocking the production of aggregation-prone peptides and proteins or on promoting the degradation of their amyloid products. 7 Recent attempts have instead concentrated on altering or delaying the aggregation process itself, which is typically achieved using compounds that bind non-covalently to different types of protein species during the aggregation reaction. 8-10 Examples of such compounds include small drug-like molecules, 23-28 molecular chaperones, 29-31 antibodies, 32,33 and nanoparticles. 34 Initially, such kinetic inhibitors were designed with the generic goal of delaying amyloid formation. [15][16][17][18][19][20][21] It has now been recognised, however, that the cytotoxicity linked to amyloid formation is not attributable to a single species. Instead, the gamut of species accessible during aggregation contribute

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Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide

Cited by 32 publications

References 42 publications

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

Infrared Nanospectroscopy Reveals the Molecular Interaction Fingerprint of an Aggregation Inhibitor with Single Aβ42 Oligomers

Thermodynamic and kinetic design principles for protein aggregation inhibitors

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