Dissecting the behaviour of β‐amyloid peptide variants during oligomerization and fibrillation

Shi, Jing-Ming; Zhang, Lin; Liu, Enqi

doi:10.1002/psc.3028

Cited by 5 publications

(7 citation statements)

References 49 publications

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“…The different Aβ preparations were characterized by western blot (Figure S1) and by transmission electron microscopy (Figure a, bottom panel). A solution of Aβ monomers (Figure a‐I) presented very few visible oligomers, while the preparation of Aβ oligomers (Figure a‐II) revealed spherical globular structures, which is compatible with previous reports (Shi, Zhang, & Liu, ). In the Aβ aggregates sample (Figure a‐III), we observed an abundant formation of fibres of up to 1 μm in length, which were absent in the two previous preparations.…”

Section: Resultssupporting

confidence: 90%

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

British J Pharmacology

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Background and Purpose Progressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. Experimental Approach We developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction. Key Results We demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738. Conclusions and Implications Our TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Resultssupporting

confidence: 90%

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

British J Pharmacology

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“…Moreover, the N-terminal truncation identified in the AD brain region affects Aβ solubility and aggregation as well . We found that the N-terminally truncated peptides Aβ(11–42) and Aβ(17–42) had comparable secondary structure contents and neurotoxicity in protofibrils (Figures and ), which is consistent with the findings that fibril formation rate and morphology differed from Aβ42 …”

Section: Discussionsupporting

confidence: 88%

“…Electrophoresis and silver staining were performed as described previously . Briefly, a 4% Tris-tricine concentrating gel and a 16.5% Tris-tricine separating gel were used in this experiment.…”

Section: Methodsmentioning

confidence: 99%

N-terminal Domain of Amyloid-β Impacts Fibrillation and Neurotoxicity

Shi

Liu

et al. 2022

ACS Omega

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Alzheimer’s disease is characterized by the presence of distinct amyloid-β peptide (Aβ) assemblies with diverse sizes, shapes, and toxicity. However, the primary determinants of Aβ aggregation and neurotoxicity remain unknown. Here, the N-terminal amino acid residues of Aβ42 that distinguished between humans and rats were substituted. The effects of these modifications on the ability of Aβ to aggregate and its neurotoxicity were investigated using biochemical, biophysical, and cellular techniques. The Aβ-derived diffusible ligand, protofibrils, and fibrils formed by the N-terminal mutational peptides, including Aβ42(R5G), Aβ42(Y10F), and rat Aβ42, were indistinguishable by conventional techniques such as size-exclusion chromatography, negative-staining transmission electron microscopy and silver staining, whereas the amyloid fibrillation detected by thioflavin T assay was greatly inhibited in vitro. Using circular dichroism spectroscopy, we discovered that both Aβ42 and Aβ42(Y10F) generated protofibrils and fibrils with a high proportion of parallel β-sheet structures. Furthermore, protofibrils formed by other mutant Aβ peptides and N-terminally shortened peptides were incapable of inducing neuronal death, with the exception of Aβ42 and Aβ42(Y10F). Our findings indicate that the N-terminus of Aβ is important for its fibrillation and neurotoxicity.

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“…Aβ 40 seeds were fibrous in a few micrometers long (Figure 2A), whereas Aβ 11−40 seeds were mainly spherical granules and irregular aggregates (Figure 2B). Barritt et al 14 observed that Aβ 11−40 aggregates were short rods with length <400 nm, but Shi et al 48 reported that Aβ 11−42 aggregates had a regular spherical structure. The different experimental results might be due to different experimental conditions, including Aβ concentration, shaking conditions, ionic strength, and temperature.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Seeding and Cross-Seeding Aggregations of Aβ₄₀ and Its N-Terminal-Truncated Peptide Aβ_11–40

et al. 2019

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In the amyloid plaques of Alzheimer’s disease (AD) patients, a large number of N-terminal-truncated amyloid β (Aβ) peptides such as Aβ11–40 have been identified in addition to the full-length Aβ peptides. However, little is known about the roles of the N-terminal-truncated peptides in AD pathological process. Herein, seeding and cross-seeding aggregations of Aβ40 and its N-terminal-truncated Aβ11–40 were investigated in the solution and on the surfaces of chips with immobilized seeds by extensive biophysical and biological analyses. The results showed that Aβ40 and Aβ11–40 aggregates could seed both homologous and heterologous aggregations of the two monomers. However, the capability and characteristics of the seeding (homologous aggregation) and cross-seeding (heterologous aggregation) were significantly different. Aβ40 seeds showed stronger acceleration effects on the aggregations than Aβ11–40 seeds and induced β-sheet-rich fibrous aggregates of similar cytotoxicities for the two monomers. This indicates that Aβ40 and Aβ11–40 had similar aggregation pathways in the seeding and cross-seeding on Aβ40 seeds. By contrast, Aβ11–40 seeds led to different aggregation pathways of Aβ40 and Aβ11–40. Pure Aβ11–40 aggregates had higher toxicity than Aβ40 aggregates, and as seeds, Aβ11–40 seeds induced Aβ40 to form aggregates of higher cytotoxicity. However, homologous Aβ11–40 aggregates induced by Aβ11–40 seeds showed lower cytotoxicity than pure Aβ11–40 aggregates. The results suggest that Aβ11–40 plays an important role in the pathological process of AD.

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Dissecting the behaviour of β‐amyloid peptide variants during oligomerization and fibrillation

Cited by 5 publications

References 49 publications

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

N-terminal Domain of Amyloid-β Impacts Fibrillation and Neurotoxicity

Seeding and Cross-Seeding Aggregations of Aβ₄₀ and Its N-Terminal-Truncated Peptide Aβ_11–40

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Dissecting the behaviour of β‐amyloid peptide variants during oligomerization and fibrillation

Cited by 5 publications

References 49 publications

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

N-terminal Domain of Amyloid-β Impacts Fibrillation and Neurotoxicity

Seeding and Cross-Seeding Aggregations of Aβ40 and Its N-Terminal-Truncated Peptide Aβ11–40

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Seeding and Cross-Seeding Aggregations of Aβ₄₀ and Its N-Terminal-Truncated Peptide Aβ_11–40