Copper Mediates Dityrosine Cross-Linking of Alzheimer's Amyloid-

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• 作者：Craig S. Atwood ; George Perry ; Hong Zeng ; Yoji Kato ; Walton D. Jones ; Ke-Qing Ling ; Xudong Huang ; Robert D. Moir ; Dandan Wang ; Lawrence M. Sayre ; Mark A. Smith ; Shu G. Chen ; and Ashley I. Bush
• 刊名：Biochemistry
• 出版年：2004
• 出版时间：January 20, 2004
• 年：2004
• 卷：43
• 期：2
• 页码：560 - 568
• 全文大小：146K
• 年卷期：v.43,no.2(January 20, 2004)
• ISSN：1520-4995

文摘

We have previously reported that amyloid Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">, 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 H₂O₂ 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 Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> [Atwood, C. S., et al. (2000) J. Neurochem. 75,1219-1233], a feature characteristic of neurotoxic soluble Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> extracted from the AD brain. Since residuescoordinating Cu are most vulnerable to oxidation, we investigated whether modifications of these residueswere responsible for Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> cross-linking. SDS-resistant oligomerization of Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> 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, Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> peptides. The addition of H₂O₂ strongly promoted Cu-induced dityrosine cross-linking ofAges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-28, Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-40, and Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">1-42, suggesting that the oxidative coupling is initiated by interaction ofH₂O₂ 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 Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> could be responsible for causingthe covalent cross-linking of Ages/gifchars/beta2.gif" BORDER=0 ALIGN="middle"> in these structures.