Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene

Shayne A. Bellingham, Debomoy Lahiri, Bryan Maloney, Sharon La Fontaine, Gerd Multhaup, James Camakaris

Research output: Contribution to journalArticle

136 Citations (Scopus)

Abstract

Alzheimer's disease is characterized by the accumulation of amyloid-β peptide, which is cleaved from the amyloid-β precursor protein (APP). Reduction in levels of the potentially toxic amyloid-β 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-β 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 over-expressing 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.

Original languageEnglish
Pages (from-to)20378-20386
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number19
DOIs
StatePublished - May 7 2004

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Amyloid beta-Protein Precursor
Copper
Alzheimer Disease
Down-Regulation
Genes
Fibroblasts
Amyloid
Proteins
Gene expression
Homeostasis
Gene Expression
Nucleic Acid Regulatory Sequences
Poisons
Metals

ASJC Scopus subject areas

  • Biochemistry

Cite this

Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene. / Bellingham, Shayne A.; Lahiri, Debomoy; Maloney, Bryan; La Fontaine, Sharon; Multhaup, Gerd; Camakaris, James.

In: Journal of Biological Chemistry, Vol. 279, No. 19, 07.05.2004, p. 20378-20386.

Research output: Contribution to journalArticle

Bellingham, Shayne A. ; Lahiri, Debomoy ; Maloney, Bryan ; La Fontaine, Sharon ; Multhaup, Gerd ; Camakaris, James. / Copper Depletion Down-regulates Expression of the Alzheimer's Disease Amyloid-β Precursor Protein Gene. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 19. pp. 20378-20386.
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