. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry. 2003 Mar 18;42(10):2768-73. PubMed.


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  1. This is a very important paper, establishing the unequivocal binding of zinc and copper to β-amyloid in actual plaques in AD tissue. Confirming earlier in-vitro structural findings (1-5), Zn and Cu coordinate Aβ subunits into an oligomeric assembly mediated by histidine bridges. The importance of this structure is that it is NOT traditional β-sheet amyloid. Actual fibrils are probably only the tip of the iceberg in AD pathology. Toxicity is caused by hypermetallated peptide, activated by binding copper, to generate hydrogen peroxide catalytically (6-8).

    We have recently purified β-amyloid from postmortem AD brain specimens and found it to contain copper and zinc, but no other metals (8), in agreement with the findings of Dong et al.

    Aβ precipitation by copper and zinc is reversible with chelation. These data encourage us to persist with hydrophobic chelators as a pharmacotherapy for AD (9-10).


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    . Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998 May 22;273(21):12817-26. PubMed.

    . Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem. 2001 Jun 8;276(23):20466-73. PubMed.

    . Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. J Biol Chem. 2003 Jan 31;278(5):2977-82. PubMed.

    . The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999 Jun 15;38(24):7609-16. PubMed.

    . Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999 Dec 24;274(52):37111-6. PubMed.

    . Metalloenzyme-like activity of Alzheimer's disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H(2)O(2). J Biol Chem. 2002 Oct 25;277(43):40302-8. PubMed.

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    . Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Jun;30(3):665-76. PubMed.

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