Dityrosine Cross-Linked Aβ Peptides:  Fibrillar β-Structure in Aβ(1-40) Is Conducive to Formation of Dityrosine Cross-Links but a Dityrosine Cross-Link in Aβ(8-14) Does Not Induce β-Structure

Abstract

Recent reports by Galeazzi and co-workers demonstrated the susceptibility of Abeta(1-42) to undergo dityrosine formation via peroxidase-catalyzed tyrosine cross-linking. We have formed dityrosine cross-links in Abeta(1-40) using these enzymatic conditions as well as a copper-H(2)O(2) method. The efficiency of dityrosine cross-link formation is strongly influenced by the aggregation state of Abeta; more dityrosine is formed when copper-H(2)O(2) or horseradish peroxidase-catalyzed oxidation is applied to fibrillar Abeta vs soluble Abeta. Once formed, dityrosine cross-links are susceptible to further oxidative processes and it appears that cross-links formed in soluble Abeta react through these pathways more readily than those formed in fibrillar Abeta. Because preorganization of fibrils affects the efficiency of dityrosine formation, we examined the effect of dityrosine formation upon local peptide conformation by assessing the solution structure of a small dityrosine dimer derived from Abeta(8-14). Two-dimensional (1)H NMR studies of the short dityrosine dimer offer no evidence of structure. Thus, the fibrillar structure of Abeta enhances formation of dityrosine cross-links, but dityrosine cross-links do not seem to enhance local secondary structure.

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

“…In an earlier investigation [39], no structural consequences after di-Tyr formation were observed, but the NMR-based structural study was limited to the very short Aβ fragment 8–14, with any stabilizing effect possibly being too small to be detected. A covalent cross-link in general is expected to stabilize structure in oligomers due to entropic reasons.…”

“…The reaction of the two Tyr10 radicals may be facilitated in the case of Aβ oligomers by the proximity of the two tyrosine residues, which is the case for oligomers with parallel register of the polypeptide chains. Indeed, the formation of di-Tyr in Aβ was easily induced in vitro mediated either by copper ions [37], [39], [40], or by peroxidase [41]. Incubation of neuroblastoma cells with monomeric Aβ1-42 is sufficient to obtain its di-Tyr linked forms efficiently internalized into the cells [37].…”

Autoantibodies to Redox-modified Oligomeric Aβ Are Attenuated in the Plasma of Alzheimer's Disease Patients

“…Redox-modified A␤ from brain and peptide oxidized in vitro contain a number of chemical modifications, including isomerization (45,46), carbonylation (47), and amino acid oxidation (10), whereas monomeric units in SDS-stable oligomeric species appear to be cross-linked by dityrosine bridges (11,31,48). The chemical modifications observed for CAPS are common to many oxidized proteins and are known to be epitopes for so-called natural autoantibodies (49,50).…”

Concentration Dependent Cu2+Induced Aggregation and Dityrosine Formation of the Alzheimer's Disease Amyloid-β Peptide

“…It is unknown at present whether the dityrosine-linked A itself or the radicals that are produced during its generation are toxic. The efficiency of dityrosine formation in fibrillar A is greater than for monomeric A (42). Dityrosine formation may occur prior to the conversion of A into amyloid (43) alternatively dityrosine formation may occur in a time-dependent manner post aggregate formation (38).…”