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


Autoria(s): Bellingham, Shayne A.; Lahiri, Debomoy K.; Maloney, Bryan; La Fontaine, Sharon; Multhaup, Gerd; Camakaris, James
Data(s)

07/05/2004

Resumo

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.<br />

Identificador

http://hdl.handle.net/10536/DRO/DU:30008690

Idioma(s)

eng

Publicador

American Society for Biochemistry and Molecular Biology

Relação

http://dro.deakin.edu.au/eserv/DU:30008690/n20040364.pdf

http://dx.doi.org/10.1074/jbc.M400805200

Direitos

2004, American Society for Biochemistry and Molecular Biology

Tipo

Journal Article