We have previously reported that amyloid A
![](/images/gifchars/beta2.gif)
, the major component of senile plaques inAlzheimer's disease (AD), binds Cu with high affinity via histidine and tyrosine residues [Atwood, C. S.,et al. (1998)
J. Biol. Chem. 273, 12817-12826; Atwood, C. S., et al. (2000)
J. Neurochem. 75, 1219-1233] and produces H
2O
2 by catalyzing the reduction of Cu(II) or Fe(III) [Huang, X., et al. (1999)
Biochemistry 38, 7609-7616; Huang, X., et al. (1999)
J. Biol. Chem. 274, 37111-37116]. Incubationwith Cu induces the SDS-resistant oligomerization of A
![](/images/gifchars/beta2.gif)
[Atwood, C. S., et al. (2000)
J. Neurochem. 75,1219-1233], a feature characteristic of neurotoxic soluble A
![](/images/gifchars/beta2.gif)
extracted from the AD brain. Since residuescoordinating Cu are most vulnerable to oxidation, we investigated whether modifications of these residueswere responsible for A
![](/images/gifchars/beta2.gif)
cross-linking. SDS-resistant oligomerization of A
![](/images/gifchars/beta2.gif)
caused by incubation withCu was found to induce a fluorescence signal characteristic of tyrosine cross-linking. Using ESI-MS anda dityrosine specific antibody, we confirmed that Cu(II) (at concentrations lower than that associatedwith amyloid plaques) induces the generation of dityrosine-cross-linked, SDS-resistant oligomers of human,but not rat, A
![](/images/gifchars/beta2.gif)
peptides. The addition of H
2O
2 strongly promoted Cu-induced dityrosine cross-linking ofA
![](/images/gifchars/beta2.gif)
1-28, A
![](/images/gifchars/beta2.gif)
1-40, and A
![](/images/gifchars/beta2.gif)
1-42, suggesting that the oxidative coupling is initiated by interaction ofH
2O
2 with a Cu(II) tyrosinate. The dityrosine modification is significant since it is highly resistant toproteolysis and is known to play a role in increasing structural strength. Given the elevated concentrationof Cu in senile plaques, our results suggest that Cu interactions with A
![](/images/gifchars/beta2.gif)
could be responsible for causingthe covalent cross-linking of A
![](/images/gifchars/beta2.gif)
in these structures.