Structural differences between amyloid beta oligomers

Breydo, Leonid; Kurouski, Dmitry; Rasool, Suhail; Milton, Saskia; Wu, Jessica; Uversky, Vladimir N.; Lednev, Igor K.; Glabe, Charles G.

doi:10.1016/j.bbrc.2016.06.122

Cited by 68 publications

(51 citation statements)

References 36 publications

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“…1C for the α-sheet design AP407, which is distinct from random coil, α-helical, and β-sheet CD spectra (29,(38)(39)(40). Contrary to our results, many assume that Aβ soluble oligomers adopt β-sheet structure in the lag phase, but a number of other studies report CD spectra very similar to the α-sheet spectra provided here (17,31,41,42). While similar spectra were obtained, they were not recognized to be α-sheet due to its novelty, as model compounds are critical to the assignment of spectra.…”

Section: Significancecontrasting

confidence: 87%

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

Shea

Hsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

140

210

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Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.

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Section: Significancecontrasting

confidence: 87%

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

Shea

Hsu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

140

210

View full text Add to dashboard Cite

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“…These non-fibrillary aggregated forms have previously been described in a number of in vitro studies including the formation of synthetic Aβ(1-40) amorphous/granular toxic aggregates at pH 5.5 and in the presence of metal ions and of unordered structures in amyloid aggregates, the occurrence of oligomeric species containing non-fibrillary β structures, and the purification of different types of oligomers such as Aβ*56 from brain homogenates [25][26][27][31][32][33] .…”

Section: Resultsmentioning

confidence: 87%

RETRACTED ARTICLE: In situ structural characterization of early amyloid aggregates in Alzheimer’s disease transgenic mice and Octodon degus

Benseny‐Cases

Álvarez-Marimon

Aso

et al. 2020

Sci Rep

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In situ structural characterization of early amyloid aggregates in Alzheimer's disease transgenic mice and Octodon degus núria Benseny-cases 1* , elena Álvarez-Marimon 2 , ester Aso 3 , Margarita carmona 3 , oxana Klementieva 4 , Dietmar Appelhans 5 , isidre ferrer 3 & Josep cladera 2* Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer's disease. In situ identification of early-stage amyloid aggregates in Alzheimer's disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice and Octodon degus for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months whereas very little formation of fibrils is found in aged Octodon degus. Finally, significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with G4-His-Mal dendrimers (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating putative therapeutic properties of G4-His-Mal dendrimers in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. no less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.

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“…Another example are the non-pore forming cylindrin-like out-of-register oligomers of Aβ 21, 22 that are also toxic and related to membrane disruption. These and other oligomer models of Aβ that have been summarized in a recent review 23 suggest looking for Aβ assemblies with three-fold and higher-fold symmetries as potential disease-causing agents. U-shaped Aβ chains can, because of steric constraints, only assemble into structures with N-fold symmetry of N ≤ 3, but the steric constraint argument does not hold for S-shaped chains.…”

Section: Introductionmentioning

confidence: 99%

Ring-like N-fold Models of Aβ42 fibrils

Hansmann

2017

Sci Rep

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When assembling as fibrils Aβ40 peptides can only assume U-shaped conformations while Aβ42 can also arrange as S-shaped three-stranded chains. We show that this allows Aβ42 peptides to assemble pore-like structures that may explain their higher toxicity. For this purpose, we develop a scalable model of ring-like assemblies of S-shaped Aβ1–42 chains and study the stability and structural properties of these assemblies through atomistic molecular dynamics simulations. We find that the proposed arrangements are in size and symmetry compatible with experimentally observed Aβ assemblies. We further show that the interior pore in our models allows for water leakage as a possible mechanism of cell toxicity of Aβ42 amyloids.

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Structural differences between amyloid beta oligomers

Cited by 68 publications

References 36 publications

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer’s disease

RETRACTED ARTICLE: In situ structural characterization of early amyloid aggregates in Alzheimer’s disease transgenic mice and Octodon degus

Ring-like N-fold Models of Aβ42 fibrils

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