The elusive nature and diagnostics of misfolded Aβ oligomers

Cerasoli, Eleonora; Ryadnov, Maxim G.; Austen, Brian

doi:10.3389/fchem.2015.00017

Cited by 25 publications

(38 citation statements)

References 74 publications

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“…Determination of the precise physiological role of the amyloidogenic polypeptides has proven to be difficult, and determining the precise mechanism of toxicity has been equally challenging . One reason for this is that it is difficult to obtain samples stable enough to generate a specific mechanism of toxicity in precise oligomeric states.…”

Section: Introductionmentioning

confidence: 99%

“…The strong interest in oligomeric species is also supported by the need for new therapeutic or diagnostic targets.Alarge number of reviews on amyloid oligomers have recently been published. [12][13][14][15][16][17][18][19][20] They focus either on single proteins or peptides as associated with one type of disease or on differenta spects of the oligomeric structures in the context of amyloid formation in general. Of special interest, for instance, is the impact of bound metal ions on the self-assembly of amyloid proteins.…”

Section: Introductionmentioning

confidence: 99%

“…

Determination of the precise physiological role of the amyloidogenicp olypeptides has proven to be difficult, and determining the precise mechanism of toxicity has been equally challenging. [13] One reason for this is that it is difficult to obtain samples stable enought og enerate as pecific mechanism of toxicity in precise oligomeric states.A myloid oligomers have demonstrated toxicity throughr eceptor-mediated, membrane, and intracellularm echanisms. Oligomeric Ab has been shown to cause cell death by receptor-mediated mechanisms, for example,b yi nteracting with the N-methyl-d-aspartate receptor (NMDAR)o rb yu p-regulating nerve growth factor (NGF), which can modulate neuronal survival by signaling through the p75

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mentioning

confidence: 99%

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An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

2016

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The deposition of amyloid in brain tissue in the context of neurodegenerative diseases involves the formation of intermediate species-termed oligomers-of lower molecular mass and with structures that deviate from those of mature amyloid fibrils. Because these oligomers are thought to be primarily responsible for the subsequent disease pathogenesis, the elucidation of their structure is of enormous interest. Nevertheless, because of the high aggregation propensity and the polydispersity of oligomeric species formed by the proteins or peptides in question, the preparation of appropriate samples for high-resolution structural methods has proven to be rather difficult. This is why theoretical approaches have been of particular importance in gaining insights into possible oligomeric structures for some time. Only recently has it been possible to achieve some progress with regard to the experimentally based structural characterization of defined oligomeric species. Here we discuss how theory and experiment are used to determine oligomer structures and what can be done to improve the integration of the two disciplines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

2016

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“…When amyloidogenesis involves long polypeptide chains (unlike prions, which tend to be short), the end result is typically a mass of elongated fibrils which disrupt the functioning of otherwise healthy tissue [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Sequence-to-Structure Relation in Proteins-Amyloidogenic Proteins with Chameleon Sequences

Banach¹,

Kalinowska²,

Konieczny³

et al. 2016

J Proteomics Bioinform

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“…2-4 However, recent evidence has identified the prefibrillar soluble oligomers of Aβ as the main neurotoxic entities. 5-13 …”

Section: Introductionmentioning

confidence: 99%

Isotope-edited FTIR reveals distinct aggregation and structural behaviors of unmodified and pyroglutamylated amyloid β peptides

Goldblatt

Matos

Gornto

et al. 2015

Phys. Chem. Chem. Phys.

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Amyloid β peptide (Aβ) is causatively associated with Alzheimer’s disease (AD), and N-terminally truncated and pyroglutamylated Aβ peptides (AβpE) exert hypertoxic effect by an unknown mechanism. Recent evidence has identified the prefibrillar oligomers of Aβ, not the fibrils, as the prevalent cytotoxic species. Structural characterization of Aβ and AβpE oligomers is therefore important for better understanding of their toxic effect. Here we have used isotope-edited Fourier transform infrared (FTIR) spectroscopy to identify the conformational changes in Aβ1-42 and AβpE3-42 upon aggregation, individually and in 1:1 molar combination. During the first two hours of exposure to aqueous buffer, the peptides undergo transition from mostly α-helical to mostly β-sheet structure. Data on peptides 13C,15N-labeled at K16L17V18 or V36G37G38V39 allowed construction of structural models for the monomer and early oligomers. The peptide monomer comprises a β-hairpin that involves residues upstream of the K16L17V18 sequence and an N-terminal α-helix. The oligomers form by non-H-bonding interactions between the β-strands of neighboring β-hairpins, in lateral or staggered manner, with the strands running parallel or antiparallel. Relative α-helical and β-sheet propensities of Aβ1-42 and AβpE3-42 depend on the ionic strength of the buffer, emphasizing the importance of ionic interactions in Aβ peptide structure and aggregation. It is inferred that N-terminal modification of AβpE3-42 affects the helix stability and thereby modulates β-sheet oligomer formation. The data thus provide new insight into the molecular mechanism of Aβ oligomerization by emphasizing the role of the N-terminal transient α-helical structure and by identifying structural constraints for molecular organization of the oligomers.

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The elusive nature and diagnostics of misfolded Aβ oligomers

Cited by 25 publications

References 74 publications

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

An Account of Amyloid Oligomers: Facts and Figures Obtained from Experiments and Simulations

Sequence-to-Structure Relation in Proteins-Amyloidogenic Proteins with Chameleon Sequences

Isotope-edited FTIR reveals distinct aggregation and structural behaviors of unmodified and pyroglutamylated amyloid β peptides

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