Synthetic dityrosine-linked β-amyloid dimers form stable, soluble, neurotoxic oligomers

Kok, W. Mei; Cottam, Jade M.; Ciccotosto, Giuseppe D.; Miles, Luke A.; Karas, John A.; Scanlon, Denis B.; Roberts, Blaine R.; Parker, Michael W.; Cappai, Roberto; Barnham, Kevin J.; Hutton, Craig A.

doi:10.1039/c3sc22295k

Cited by 47 publications

(75 citation statements)

References 32 publications

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“…Although these studies provided the first information about the unique aggregation properties of Aβ dimers, the Aβ sequence does not naturally contain cysteines. The initial attempts to study dimers held together by cross-links that could occur in AD were restricted to dityrosine cross-linked Aβ40 (29, 40). Like cystine cross-linked dimers, the self-assembled structure and aggregation kinetics of Aβ40DiY was found to be distinct from that of Aβ40 monomer.…”

Section: Introductionmentioning

confidence: 99%

The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

O’Malley

Witbold²,

Linse

et al. 2016

Biochemistry

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Extracts of Alzheimer's disease (AD) brain that contain what appear to be SDS-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated from Aβ monomer, consist primarily of Aβ42 and resist denaturation by powerful chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in only one of two different ways - either by the formation of a dityrosine (DiY) or an isopeptide ε-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then applied a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar aggregates formed by Aβ monomer. These results suggest that Aβ dimers allow the formation of soluble aggregates akin to those in aqueous extracts of AD brain. Thus it seems that Aβ dimers may play an important role in determining the formation of soluble rather than insoluble aggregates.

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Section: Introductionmentioning

confidence: 99%

The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

O’Malley

Witbold²,

Linse

et al. 2016

Biochemistry

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“…Incubation of neuroblastoma cells with monomeric Aβ1-42 is sufficient to obtain its di-Tyr linked forms efficiently internalized into the cells [37]. Induction of di-Tyr in synthetic Aβ1-42 preparations led to a marked, 620-fold increase in the number of cofilin-saturated actin bundles [17], an alternative histopathological AD hallmark [42] and in Aβ1-40 to increased neurotoxicity in a neuronal cell line viability assay [43].…”

Section: Introductionmentioning

confidence: 99%

Di-Tyrosine Cross-Link Decreases the Collisional Cross-Section of Aβ Peptide Dimers and Trimers in the Gas Phase: An Ion Mobility Study

et al. 2014

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Oligomeric forms of Aβ peptide are most likely the main synaptotoxic and neurotoxic agent in Alzheimer’s disease. Toxicity of various Aβ oligomeric forms has been confirmed in vivo and also in vitro. However, in vitro preparations were found to be orders of magnitude less toxic than oligomers obtained from in vivo sources. This difference can be explained by the presence of a covalent cross-link, which would stabilize the oligomer. In the present work, we have characterized the structural properties of Aβ dimers and trimers stabilized by di- and tri-tyrosine cross-links. Using ion mobility mass spectrometry we have compared the collisional cross-section of non-cross-linked and cross-linked species. We have found that the presence of cross-links does not generate new unique forms but rather shifts the equilibrium towards more compact oligomer types that can also be detected for non-cross-linked peptide. In consequence, more extended forms, probable precursors of off-pathway oligomeric species, become relatively destabilized in cross-linked oligomers and the pathway of oligomer evolution becomes redirected towards fibrillar structures.

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“…Therefore, in principle, using the chemically-tethering method, we can isolate defined and unique Ab oligomers in an assembly state-pure form using affordable analytical instruments. There are several previous reports of chemically-tethered Ab oligomers, but they are limited to dimers [7][8][9][10][11] and there has been no report on the synthesis of oligomers larger than dimers, as the synthesis of trimers is considered more difficult than that of dimers. Some reports, however, advocate an important role for Ab trimers in Ab pathogenicity.…”

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confidence: 99%

“…The present findings are consistent with this hypothesis, as well as chemically synthesized Ab dimers with stronger aggregative properties than those of the corresponding monomers. 7,[9][10][11] Additionally, the activities of known aggregation inhibitors of Ab were investigated to identify compounds with the potential to Figure 4. (a) ThT assay (k ex = 440 ± 5 nm, k em = 480 ± 10 nm).…”

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confidence: 99%

Synthesis of chemically-tethered amyloid-β segment trimer possessing amyloidogenic properties

Shinoda

Sohma

Kanai

2015

Bioorganic & Medicinal Chemistry Letters

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As amyloid-β (Aβ) undergoes dynamic aggregation, it is impossible to isolate ('hook') the transient Aβ oligomer in an assembly state-pure form (e.g., sole Aβ dimer, trimer, tetramer, etc.). Obtaining such a pure Aβ oligomer would allow us to establish an in vitro system to perform a more detailed investigation of the pathogenic properties of the oligomer. A chemically-tethered Aβ oligomer, constructed only by covalent bonds, could satisfy this demand. Here we designed a chemically-tethered trimer of a pathogenic Aβ fragment (Aβ25-35) (1) and successfully generated it in situ from its precursor (4), a water-soluble and non-aggregative O-acyl isopeptide of 1, in neutral aqueous media. Chemically-tethered 1 possessed stronger amyloidogenic properties, that is, potential for β-sheet structure, fibril formation, and cytotoxicity, than the corresponding monomer Aβ25-35 (6). Trimerization of Aβ25-35 sequence might affect both the aggregative properties and cytotoxicity, based on the present results. This work opens the door for chemical synthesis of oligomers bigger than trimers in an assembly state-pure form, allowing for identification of the most toxic Aβ oligomer.

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Synthetic dityrosine-linked β-amyloid dimers form stable, soluble, neurotoxic oligomers

Cited by 47 publications

References 32 publications

The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

Di-Tyrosine Cross-Link Decreases the Collisional Cross-Section of Aβ Peptide Dimers and Trimers in the Gas Phase: An Ion Mobility Study

Synthesis of chemically-tethered amyloid-β segment trimer possessing amyloidogenic properties

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