Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Sarroukh, Rabia; Cerf, Emilie; Derclaye, Sylvie; Dufrêne, Yves F.; Goormaghtigh, Erik; Ruysschaert, Jean Marie; Raussens, Vincent

doi:10.1007/s00018-010-0529-x

Cited by 137 publications

(141 citation statements)

References 58 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…The ratios of Ab42 (in mM) to SPE product concentration (in mg ml View Online parallel (fibrils) b-sheet content for Ab42 along the aggregation process. 16,34 In support of the current findings, it has been shown that anti-parallel b-sheet structure could also be the signature of toxicity for HET-s(218-289) prion peptide.…”

supporting

confidence: 86%

See 1 more Smart Citation

Modulation of amyloid-β 1-42 structure and toxicity by proline-rich whey peptides

et al. 2013

Self Cite

View full text Add to dashboard Cite

A proline-rich peptide product prepared from bovine whey protein that was enriched in several hydrophobic amino acids including proline (whey proline-rich peptide, wPRP) was shown to modulate the folding pathway of human amyloid beta peptide 1-42 (Ab42) into oligomers. Concentrationdependent changes in ThT-binding to Ab42 by wPRP indicated suppression of oligomerisation, that was supported by Transmission Electron Microscopy. Suppression of b-sheet and specifically, antiparallel b-sheet structures by wPRP was demonstrated by ATR-FTIR spectroscopy, where evidence for capacity of wPRP to dissociate pre-existing b-sheet structures in Ab42 was also apparent. Suppression of anti-parallel b-sheets of oligomeric Ab42 was associated with rescue of yeast and SH-SY5Y neuronal cells providing important evidence for the association between anti-parallel b-sheet structure and oligomer toxicity. It was proposed that the interaction of wPRP with Ab42 interfered with the antiparallel folding pathway of oligomeric Ab42 and ultimately produced 'off-pathway' structures of lowered total b-sheet content, with attenuated cellular toxicity. IntroductionIn 2010, cases of dementia including Alzheimer's disease (AD) affected 35.6 million people worldwide with predicted increase of 65.7 million to 115.4 million from 2030 to 2050, according to Alzheimer's Disease International, the worldwide federation of Alzheimer's Associations. The substantial projected social and economic burden of AD world-wide has driven the need for evaluation of the costs of the illness, the cost-effectiveness of interventions and ultimately, the implementation of public policies and services.1 Disease-modifying therapies remain a high priority for development and use in AD care, however the current absence of effective disease-modifying therapies reflects the significant challenge posed by this goal. Furthermore, as preventative measures are likely to be most effective in presymptomatic stages of disease, diet and lifestyle interventions are favoured at this stage. Of relevance to this study is the precedent set by the proline-rich peptide extract prepared from ovine colostrums known as 'Colostrinin' 2 for which anti-fibril and other neuroprotective bioactivities have been extensively reported.Amyloid beta (Ab) is a 40 or 42 amino acid cleavage product of Amyloid Precursor Protein (APP) produced in low levels in the normal ageing brain. It is the major component of senile extracellular plaques in the brain of AD patients and increased levels of Ab42 and its self-aggregation in the brain are key events thought to be responsible for the progressive cognitive decline associated with AD.3 In addition to the heterogeneity and toxic variability of extra-cellular amyloid structures, 4 disease progression has also been attributed to the retention of intracellular Ab42.5 Amyloid fibrils comprise highly ordered, cross-bsheet arrays that elongate into long fibrils and aggregate as tangled plaques. Oligomeric Ab42 represents a low mass, soluble form of Ab42 produced by an ear...

show abstract

supporting

confidence: 86%

“…33 However, formation of meta-stable oligomeric Ab42 represents an early competing folding pathway 6 characterised by anti-parallel b-sheet structure. 34 In this study, Ab42 preparations modelled the earliest stages of oligomer assembly from aggregate-free stocks 16 over a standard incubation period of 20-24 h.…”

mentioning

confidence: 99%

Modulation of amyloid-β 1-42 structure and toxicity by proline-rich whey peptides

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Meanwhile, consistent observations have been reported for different Aβ(1-40) and Aβ(1-42) peptide preparations and for samples from different laboratories. 24,29,71,72 Further, they relate to longstanding evidence on SH3 domain, which produces non-fibrillar aggregates with a well-resolved amide I′ peak at 1684 cm − 1 in D 2 O solution, while no such peak is seen with fibrils. 73 Lysozyme oligomers have also been show to incorporate a peak at 1688 cm − 1 in D 2 O solutions.…”

Section: Role Of Oligomers For the Mechanism Of Fibril Formationmentioning

confidence: 83%

Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Fändrich

2012

Journal of Molecular Biology

312

View full text Add to dashboard Cite

“…43) Structural analyses by isotope-edited Fourier transform IR spectroscopy (FTIR) and solid-state NMR suggested that a toxic form of oligomeric Aβs had anti-parallel β-sheets. 44,45) Furthermore, the fibrils formed on the membrane are significantly cytotoxic, whereas the fibrils formed in solution are less toxic. 13,46) Since the major content of a singly isolated Aβ is α-helix, 47,48) structural transformation into a β-sheet of Aβ will be related to the toxic fibril form.…”

Section: Discussionmentioning

confidence: 99%

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

2018

View full text Add to dashboard Cite

Aggregation and complex formation of amyloid beta (Aβ) peptides on a neuronal cell membrane is a hallmark of neuro-disturbance diseases. In this work, we performed molecular dynamics (MD) simulations to investigate the initial stage of interactions of multiple Aβ 42 peptides on a GM1 ganglioside-containing membrane that mimics a micro-domain on the neuronal cell surface. Conformational changes of Aβs due to adhesion on the membrane and subsequent molecular interactions among the Aβs were monitored. It was suggested from results of the two 1.0 µs simulation trials that stable complexes of Aβ peptides were not rapidly generated but that a steady binding of two Aβs was gradually formed. Observation of two Aβs that will be a complex with steady binding revealed that one Aβ was bound to the membrane surface, while the other was attached to the first one without strong contact with the membrane. The motion of the first one was restricted and its conformational change was limited, with the basic side-chains of Arg5 and Lys28 working as anchors to hold the Aβ helix region on the membrane. In contrast, the second one had high flexibility and showed diversity in its conformation. The second Aβ can search for an energetically favorable binding position on the first one. A parallel β-sheet structure was formed between the C-terminal sides of the two Aβs. Ala30 was critically important to lead the stable β-sheet conformation at the C-terminal hydrophobic domains of Aβs. In the N-terminal sides, helix structures were kept in both Aβs.Key words amyloid beta peptide; molecular dynamics simulation; membrane surface; molecular interaction; conformational change; complex structure Aggregation of amyloid beta (Aβ)-peptides is closely linked to several neurodegeneration diseases including Alzheimer's disease (AD).1-3) Aβ is a small peptide consisting of typically 39-43 amino acid residues and it is a normal product of cellular metabolism from amyloid precursor protein (APP) due to the successive proteolytic action by β-and γ-secretases. 4,5) Aggregation and resultant transformation of Aβ peptides into insoluble misfolding proteins is a pathological hallmark of neurodegeneration diseases in the brain.4) The most commonly observed forms of toxic Aβs are comprised of 40 and/or 42 residues. Both of them show an affinity to a lipid membrane, but Aβ 42 (a.a. 1-42) is more likely to form amyloid fibrils. 6)This strong tendency of Aβ 42 to aggregate is related to two additional hydrophobic amino acids at its C-terminal end. 7)According to an in vivo study, 8) soluble Aβ oligomers were sequestered from brain interstitial fluid onto brain membranes more rapidly than non-toxic monomers and they were strongly bound to GM1-ganglioside on the cellular membranes. GM1 is likely to form a cluster on a membrane containing sphingomyelin (SM) and cholesterol (Chol). A GM1 cluster has a hydrophobic surface and a negatively charged area due to the condensation of glycans. Many in vitro studies have shown an acceleration of Aβ aggregation on lipid micro-d...

show abstract

Transformation of amyloid β(1–40) oligomers into fibrils is characterized by a major change in secondary structure

Cited by 137 publications

References 58 publications

Modulation of amyloid-β 1-42 structure and toxicity by proline-rich whey peptides

Modulation of amyloid-β 1-42 structure and toxicity by proline-rich whey peptides

Oligomeric Intermediates in Amyloid Formation: Structure Determination and Mechanisms of Toxicity

Simulation Study on Complex Conformations of Aβ<sub>42</sub> Peptides on a GM1 Ganglioside-Containing Lipid Membrane

Contact Info

Product

Resources

About