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Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease.
J Biol Chem. 2004 Dec 10; 279(50):51958-64.JB

Abstract

The key protein in Alzheimer's disease, the amyloid precursor protein (APP), is a ubiquitously expressed copper-binding glycoprotein that gives rise to the Abeta amyloid peptide. Whereas overexpression of APP results in significantly reduced brain copper levels in three different lines of transgenic mice, knock-out animals revealed increased copper levels. A provoked rise in peripheral levels of copper reduced concentrations of soluble amyloid peptides and resulted in fewer pathogenic Abeta plaques. Contradictory evidence has been provided by the efficacy of copper chelation treatment with the drug clioquinol. Using a yeast model system, we show that adding clioquinol to the yeast culture medium drastically increased the intracellular copper concentration but there was no significant effect observed on zinc levels. This finding suggests that clioquinol can act therapeutically by changing the distribution of copper or facilitating copper uptake rather than by decreasing copper levels. The overexpression of the human APP or APLP2 extracellular domains but not the extracellular domain of APLP1 decreased intracellular copper levels. The expression of a mutant APP deficient for copper binding increased intracellular copper levels several-fold. These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease.

Authors+Show Affiliations

Freie Universitaet Berlin, Institut fuer Chemie/Biochemie, Thielallee 63, D-14195 Berlin, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15465814

Citation

Treiber, Carina, et al. "Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease." The Journal of Biological Chemistry, vol. 279, no. 50, 2004, pp. 51958-64.
Treiber C, Simons A, Strauss M, et al. Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. J Biol Chem. 2004;279(50):51958-64.
Treiber, C., Simons, A., Strauss, M., Hafner, M., Cappai, R., Bayer, T. A., & Multhaup, G. (2004). Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. The Journal of Biological Chemistry, 279(50), 51958-64.
Treiber C, et al. Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease. J Biol Chem. 2004 Dec 10;279(50):51958-64. PubMed PMID: 15465814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clioquinol mediates copper uptake and counteracts copper efflux activities of the amyloid precursor protein of Alzheimer's disease. AU - Treiber,Carina, AU - Simons,Andreas, AU - Strauss,Markus, AU - Hafner,Mathias, AU - Cappai,Roberto, AU - Bayer,Thomas A, AU - Multhaup,Gerd, Y1 - 2004/09/30/ PY - 2004/10/7/pubmed PY - 2005/2/3/medline PY - 2004/10/7/entrez SP - 51958 EP - 64 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 50 N2 - The key protein in Alzheimer's disease, the amyloid precursor protein (APP), is a ubiquitously expressed copper-binding glycoprotein that gives rise to the Abeta amyloid peptide. Whereas overexpression of APP results in significantly reduced brain copper levels in three different lines of transgenic mice, knock-out animals revealed increased copper levels. A provoked rise in peripheral levels of copper reduced concentrations of soluble amyloid peptides and resulted in fewer pathogenic Abeta plaques. Contradictory evidence has been provided by the efficacy of copper chelation treatment with the drug clioquinol. Using a yeast model system, we show that adding clioquinol to the yeast culture medium drastically increased the intracellular copper concentration but there was no significant effect observed on zinc levels. This finding suggests that clioquinol can act therapeutically by changing the distribution of copper or facilitating copper uptake rather than by decreasing copper levels. The overexpression of the human APP or APLP2 extracellular domains but not the extracellular domain of APLP1 decreased intracellular copper levels. The expression of a mutant APP deficient for copper binding increased intracellular copper levels several-fold. These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15465814/Clioquinol_mediates_copper_uptake_and_counteracts_copper_efflux_activities_of_the_amyloid_precursor_protein_of_Alzheimer's_disease_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15465814 DB - PRIME DP - Unbound Medicine ER -