Dong J, Canfield JM, Mehta AK, Shokes JE, Tian B, Childers WS, Simmons JA, Mao Z, Scott RA, Warncke K, Lynn DG. Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity. Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13313-8. PubMed.

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  1. The work by Dong et al. adds further knowledge on Cu ion coordination regulating fibril formation. The authors show that the coordination of a distinct variant of an Aβ-Cu complex is required to induce toxicity as demonstrated by a monocyte enhancer factor 2 assay in a dopaminergic neuron cell line. There was, however, no difference compared to Aβ1-42. In this context, they demonstrated that N-terminal acetylation and H14A substitution alters metal coordination and fibril assembly. The conclusion was that metal-ion coordination and not simply metal-ion binding may be critical in the etiology of Alzheimer disease (AD) and possibly other related diseases.

    Whether Cu has a toxic or beneficial effect on pathological processes in AD is a matter of an ongoing and of course controversial scientific debate. On one side, there are many reports showing toxicity of Aβ-Cu complexes in vitro (including the paper by Dong et al.). In vivo treatment with clioquinol, a Cu-Zn chelator, inhibited β amyloid accumulation in Tg2576 transgenic mice (1). Accordingly, trace amounts of Cu have been reported to trigger plaque pathology in a rabbit model (2). On the other side, increasing brain Cu levels by genetic or dietary means had beneficial effects regarding amyloid load and live duration in two different AD models (3,4). These findings clearly show that the Cu biology in AD is complex. More important, we should keep in mind that we are dealing here with in vivo and in vitro model systems, which reflect only partly the situation in AD brain. It may be of interest, therefore, that we have recently completed a 12-month clinical phase 2 trial (double-blind and placebo controlled) with 70 AD patients, who received daily 8 mg Cu-Orotate. We hope that this trial will demonstrate whether modulation of Cu levels has any relevance in a clinical setting.

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    Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11065-9. PubMed.

    Bayer TA, Schäfer S, Simons A, Kemmling A, Kamer T, Tepest R, Eckert A, Schüssel K, Eikenberg O, Sturchler-Pierrat C, Abramowski D, Staufenbiel M, Multhaup G. Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-92. PubMed.

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