2010
DOI: 10.1073/pnas.1001740107
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Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

Abstract: Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer's disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a doublecysteine mutant (called AβCC) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ 40 CC and Aβ 42 CC both spontaneou… Show more

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Cited by 323 publications
(453 citation statements)
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“…For instance, the first ␤-strand of A␤ oligomers and protofibrils is significantly shorter than that in mature A␤ fibrils and has to elongate during the conversion from protofibrils to mature fibrils (20). In addition, many questions about the tertiary structure, the fibrillation process, and the conversion from one intermediate to another are still unanswered.Härd and co-workers have resolved the structure of A␤(1-40) oligomers stabilized by an Affibody and also proposed a model for the arrangement of the two ␤-strands (14,15,22). In this model, these ␤-strands form intramolecular hydrogen bonds in the oligomeric state, in contrast to the known intermolecular hydrogen-bonded structure of mature A␤ fibrils (8,11,23).…”
mentioning
confidence: 96%
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“…For instance, the first ␤-strand of A␤ oligomers and protofibrils is significantly shorter than that in mature A␤ fibrils and has to elongate during the conversion from protofibrils to mature fibrils (20). In addition, many questions about the tertiary structure, the fibrillation process, and the conversion from one intermediate to another are still unanswered.Härd and co-workers have resolved the structure of A␤(1-40) oligomers stabilized by an Affibody and also proposed a model for the arrangement of the two ␤-strands (14,15,22). In this model, these ␤-strands form intramolecular hydrogen bonds in the oligomeric state, in contrast to the known intermolecular hydrogen-bonded structure of mature A␤ fibrils (8,11,23).…”
mentioning
confidence: 96%
“…Härd and co-workers have resolved the structure of A␤(1-40) oligomers stabilized by an Affibody and also proposed a model for the arrangement of the two ␤-strands (14,15,22). In this model, these ␤-strands form intramolecular hydrogen bonds in the oligomeric state, in contrast to the known intermolecular hydrogen-bonded structure of mature A␤ fibrils (8,11,23).…”
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confidence: 96%
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“…Therefore, engineered disulfide-bonds have been introduced into synthetic Aβ to study Aβ toxicity and oligomerization properties. 14,15 In these studies, one or two cysteines were introduced into the Aβ polypeptide chain, leading to either inter-or intramolecular disulfide bonds after oxidation. 14,15 However, when introducing intermolecular disulfide bonds in cell-free synthetic Aβ, the oxidative bond formation and Aβ-aggregation are competing processes, and the fast development of fibrils or insoluble aggregation no longer allows disulfide-bond formation to stabilize soluble oligomers.…”
mentioning
confidence: 99%