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

Abstract

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.

Structures of the Alzheimer’s Wild-Type Aβ1-40 Dimer from Atomistic Simulations

“…[43][44][45][46][47] Also our ensemble reveals the existence of off-pathway configurations with mixed αβ or all α contents, which have already been discussed in atomistic REMD-OPLS simulations of the Aβ1-42 dimer 28 and a NMR-guided metadynamics simulation of the Aβ1-40 monomer. 48 The finding of compact and extended dimer configurations with small and large end-to-end distances of the peptides is also consistent with recent IM-MS analysis of Aβ1-40 oligomers, 9,37 and all-atom simulations of the Aβ1-28 and Aβ1-40 monomers in explicit solvent. 17,48 Recent experiments and simulations have emphasized the role of the Nterminus in self-assembly.…”

Dityrosine cross-link trapping of amyloid-β intermediates reveals that self-assembly is required for Aβ-induced cytotoxicity

“…Instead, it stabilises or traps Aβ assemblies and delay further elongation. This is supported by previous reports that showed that DiY cross-linked Aβ are slow to fibrilise and form long-lived soluble oligomeric aggregates [19][20][21][22] . Mass-spectrometry studies have revealed that DiY cross-linking leads to the stabilisation of Aβ40 in compact oligomeric species 22 , which is in strong support of our findings.…”

“…Cu 2+ /H202) (MCO) and peroxidase-catalysed oxidation. Some studies have shown that DiY cross-linking of both Ab40 and Ab42 results in the generation of toxic Ab assemblies with reduced assembly speed [17][18][19][20][21][22] , inhibit Ab40 assembly, especially in highly oxidative environments 23 or induce the formation of Ab42 non-amyloidogenic aggregates when catalysed with a high concentration of Cu 2+ 24 . Whether DiY cross-linking is a driver, facilitator or inhibitor of Ab self-assembly is still not clear from these studies.…”

Membrane‐bound tetramer and trimer Aβ oligomeric species correlate with toxicity towards cultured neurons

“…) others have observed SDS stable oligomeric species were not artificially induced by SDS (Sitkiewicz et al . ). Our results support the latter observation based on our own control experiments, mass spectral data analysis and cell binding analysis following treatment with oligomeric Aβ species.…”