Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G, Carey PR.
Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence.
Biochemistry. 2003 Mar 18;42(10):2768-73.
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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).
References:1. Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel J-P, Gusella JF, Beyreuther K, Masters CL, Tanzi RE. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994 Sep 2;265(5177):1464-7.
2. Huang X, Atwood CS, Moir RD, Hartshorn MA, Vonsattel J-P, Tanzi RE, Bush AI. Zinc-induced Alzheimer's Abeta1-40 aggregation is mediated by conformational factors. J Biol Chem. 1997 Oct 17;272(42):26464-70.
3. Atwood CS, Moir RD, Huang X, Bacarra NME, Scarpa RC, Romano DM, Hartshorn MA, Tanzi RE, Bush AI. 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.
4. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ. 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.
5. Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ. 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.
6. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI. The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999 Jun 15;38(24):7609-16.
7. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall J, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI. 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.
8. Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, Cappai R, Masters CL, Tanzi RE, Inestrosa NC, Bush AI. 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.
9. Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS, Tanzi RE, Masters CL, Bush AI. Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion.
J Biol Chem. 1999 Aug 13;274(33):23223-8.
10. Cherny RA, Atwood CS, Xilinas X, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y-S, Huang X, Goldstein LE, Moir RD, Lim JT, Zheng H, Beyreuther K, Tanzi RE, Masters CL, Bush AI. 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.