Copper depletion down-regulates expression of the Alzheimer's Disease amyloid-ß precursor protein gene

Bellingham, Shayne A., Lahiri, Debomoy K., Maloney, Bryan, La Fontaine, Sharon, Multhaup, Gerd and Camakaris, James 2004, Copper depletion down-regulates expression of the Alzheimer's Disease amyloid-ß precursor protein gene, Journal of biological chemistry, vol. 279, no. 19, pp. 20378-20386, doi: 10.1074/jbc.M400805200.

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Title Copper depletion down-regulates expression of the Alzheimer's Disease amyloid-ß precursor protein gene
Author(s) Bellingham, Shayne A.
Lahiri, Debomoy K.
Maloney, Bryan
La Fontaine, SharonORCID iD for La Fontaine, Sharon
Multhaup, Gerd
Camakaris, James
Journal name Journal of biological chemistry
Volume number 279
Issue number 19
Start page 20378
End page 20386
Publisher American Society for Biochemistry and Molecular Biology
Place of publication Bethesda, Md.
Publication date 2004-05-07
ISSN 0021-9258
Summary Alzheimer's disease is characterized by the accumulation of amyloid-ß peptide, which is cleaved from the amyloid-ß precursor protein (APP). Reduction in levels of the potentially toxic amyloid-ß has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-ß in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein. MNK deletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulated APP gene expression. Furthermore, APP promoter deletion constructs identified the copper-regulatory region between -490 and +104 of the APP gene promoter in both basal MNK overexpressing cells and in copper-chelated MNK deletion cells. Overall these data support the hypothesis that copper can regulate APP expression and further support a role for APP to function in copper homeostasis. Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease.
Language eng
DOI 10.1074/jbc.M400805200
Field of Research 060405 Gene Expression (incl Microarray and other genome-wide approaches)
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2004, American Society for Biochemistry and Molecular Biology
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Document type: Journal Article
Collection: School of Biological and Chemical Sciences
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