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Intracellular copper deficiency increases amyloid-β; secretion by diverse mechanisms

journal contribution
posted on 2008-05-15, 00:00 authored by M Cater, K McInnes, Q X Li, I Volitakis, Sharon La FontaineSharon La Fontaine, J Mercer, A Bush
In Alzheimer's disease there is abnormal brain copper distribution, with accumulation of copper in amyloid plaques and a deficiency of copper in neighbouring cells. Excess copper inhibits Aβ (amyloid β-peptide)  production, but the effects of deficiency have not yet been determined. We therefore studied the effects of modulating intracellular copper levels on the processing of APP (amyloid precursor protein) and the production of Aβ. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)α into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPβ and produced more amyloidogenic β-cleaved APP C-termini (C99). The level of Aβ secreted from copper-deficient fibroblasts was however regulated and limited by α-secretase cleavage. APP can be processed by both α- and β-secretase, as copper-deficient fibroblasts secreted sAPPβ exclusively, but produced primarily α-cleaved APP C-terminal fragments (C83). Copper deficiency also markedly reduced the steady-state level of APP mRNA whereas the APP protein level remained constant, indicating that copper deficiency may accelerate APP translation. Copper deficiency in human neuroblastoma cells significantly increased the level of Aβ secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Aβ secretion by either influencing APP cleavage or by inhibiting its degradation, with the mechanism dependent on cell type. Overall our results suggest that correcting brain copper imbalance represents a relevant therapeutic target for Alzheimer's disease.



Biochemical journal




part 1


141 - 152


Portland Press Ltd


London, England







Publication classification

C1 Refereed article in a scholarly journal

Copyright notice

2008, The Authors