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

Cater, Michael A., McInnes, Kelly, Li, Qiao-Xin, Volitakis, Irene, La Fontaine, Sharon, Mercer, Julian and Bush, Ashley 2008, Intracellular copper deficiency increases amyloid-β; secretion by diverse mechanisms, Biochemical journal, vol. 412, no. part 1, pp. 141-152, doi: 10.1042/BJ20080103.

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Title Intracellular copper deficiency increases amyloid-β; secretion by diverse mechanisms
Author(s) Cater, Michael A.
McInnes, Kelly
Li, Qiao-Xin
Volitakis, Irene
La Fontaine, SharonORCID iD for La Fontaine, Sharon
Mercer, Julian
Bush, Ashley
Journal name Biochemical journal
Volume number 412
Issue number part 1
Start page 141
End page 152
Total pages 12
Publisher Portland Press Ltd
Place of publication London, England
Publication date 2008-05-15
ISSN 0264-6021
Keyword(s) alzheimer's disease
amyloid precursor protein (APP)
menkes protein (ATP7A)
Summary 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.
Language eng
DOI 10.1042/BJ20080103
Field of Research 060199 Biochemistry and Cell Biology not elsewhere classified
Socio Economic Objective 0 Not Applicable
HERDC Research category C1 Refereed article in a scholarly journal
HERDC collection year 2008
Copyright notice ©2008, The Authors
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