{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:18:43Z","timestamp":1790266723274,"version":"4.1.0"},"reference-count":54,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,5,15]]},"abstract":"<jats:p>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 A\u03b2 (amyloid \u03b2-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 A\u03b2. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)\u03b1 into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPP\u03b2 and produced more amyloidogenic \u03b2-cleaved APP C-termini (C99). The level of A\u03b2 secreted from copper-deficient fibroblasts was however regulated and limited by \u03b1-secretase cleavage. APP can be processed by both \u03b1- and \u03b2-secretase, as copper-deficient fibroblasts secreted sAPP\u03b2 exclusively, but produced primarily \u03b1-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 A\u03b2 secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate A\u03b2 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.<\/jats:p>","DOI":"10.1042\/bj20080103","type":"journal-article","created":{"date-parts":[[2008,4,25]],"date-time":"2008-04-25T13:56:03Z","timestamp":1209131763000},"page":"141-152","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Intracellular copper deficiency increases amyloid-\u03b2 secretion by diverse mechanisms"],"prefix":"10.1042","volume":"412","author":[{"given":"Michael\u00a0A.","family":"Cater","sequence":"first","affiliation":[{"name":"Oxidation Biology Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly\u00a0T.","family":"McInnes","sequence":"additional","affiliation":[{"name":"Centre for Cellular and Molecular Biology, Deakin University, Burwood, Victoria 3125, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao-Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Volitakis","sequence":"additional","affiliation":[{"name":"Oxidation Biology Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"La\u00a0Fontaine","sequence":"additional","affiliation":[{"name":"Centre for Cellular and Molecular Biology, Deakin University, Burwood, Victoria 3125, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian\u00a0F.\u00a0B.","family":"Mercer","sequence":"additional","affiliation":[{"name":"Centre for Cellular and Molecular Biology, Deakin University, Burwood, Victoria 3125, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley\u00a0I.","family":"Bush","sequence":"additional","affiliation":[{"name":"Oxidation Biology Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia"},{"name":"Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2008,4,25]]},"reference":[{"key":"2021112214594040700_B1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3233\/JAD-2006-102-303","article-title":"Metals and Alzheimer's disease","volume":"10","author":"Adlard","year":"2006","journal-title":"J. Alzheimers Dis."},{"key":"2021112214594040700_B2","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/0006-291X(84)91209-9","article-title":"Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein","volume":"122","author":"Glenner","year":"1984","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021112214594040700_B3","doi-asserted-by":"crossref","first-page":"4245","DOI":"10.1073\/pnas.82.12.4245","article-title":"Amyloid plaque core protein in Alzheimer's disease and Down's syndrome","volume":"82","author":"Masters","year":"1985","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112214594040700_B4","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1126\/science.8073293","article-title":"Rapid induction of Alzheimer A \u03b2-amyloid formation by zinc","volume":"265","author":"Bush","year":"1994","journal-title":"Science"},{"key":"2021112214594040700_B5","doi-asserted-by":"crossref","first-page":"23223","DOI":"10.1074\/jbc.274.33.23223","article-title":"Aqueous dissolution of Alzheimer's disease A\u03b2-amyloid deposits by biometal depletion","volume":"274","author":"Cherny","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B6","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0022-510X(98)00092-6","article-title":"Copper, iron and zinc in Alzheimer's disease senile plaques","volume":"158","author":"Lowell","year":"1998","journal-title":"J. Neurol. Sci."},{"key":"2021112214594040700_B7","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1021\/bi0272151","article-title":"Metal binding and oxidation of amyloid-\u03b2 within isolated senile plaque cores: Raman microscopic evidence","volume":"42","author":"Dong","year":"2003","journal-title":"Biochemistry"},{"key":"2021112214594040700_B8","doi-asserted-by":"crossref","first-page":"40302","DOI":"10.1074\/jbc.M206428200","article-title":"Metalloenzyme-like activity of Alzheimer's disease \u03b2-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2","volume":"277","author":"Opazo","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B9","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/S0896-6273(01)00317-8","article-title":"Treatment with a copper-zinc chelator markedly and rapidly inhibits \u03b2-amyloid accumulation in Alzheimer's disease transgenic mice","volume":"30","author":"Cherny","year":"2001","journal-title":"Neuron"},{"key":"2021112214594040700_B10","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.neurobiolaging.2004.01.005","article-title":"The lipophillic metal chelator DP-109 reduces amyloid pathology in brains of human \u03b2-amyloid precursor protein transgenic mice","volume":"25","author":"Lee","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"2021112214594040700_B11","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1046\/j.1471-4159.2000.0751219.x","article-title":"Characterization of copper interactions with Alzheimer amyloid \u03b2-peptides: Identification of an attomolar-affinity copper binding site on amyloid \u03b21-42","volume":"75","author":"Atwood","year":"2000","journal-title":"J. Neurochem."},{"key":"2021112214594040700_B12","doi-asserted-by":"crossref","first-page":"7609","DOI":"10.1021\/bi990438f","article-title":"The A\u03b2 peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction","volume":"38","author":"Huang","year":"1999","journal-title":"Biochemistry"},{"key":"2021112214594040700_B13","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/359325a0","article-title":"Isolation and quantification of soluble Alzheimer's \u03b2-peptide from biological fluids","volume":"359","author":"Seubert","year":"1992","journal-title":"Nature"},{"key":"2021112214594040700_B14","doi-asserted-by":"crossref","first-page":"17401","DOI":"10.1074\/jbc.M300629200","article-title":"Structure of the Alzheimer's disease amyloid precursor protein copper binding domain. A regulator of neuronal copper homeostasis","volume":"278","author":"Barnham","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B15","first-page":"423","article-title":"Gene knockout of amyloid precursor protein and amyloid precursor-like protein-2 increases cellular copper levels in primary mouse cortical neuron and embryonic fibroblasts","volume":"91","author":"Bellingham","year":"2004","journal-title":"J. Neurosci."},{"key":"2021112214594040700_B16","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0006-8993(99)01861-2","article-title":"Copper levels are increased in the cerebral cortex and liver of APP and APLP2 knockout mice","volume":"842","author":"White","year":"1999","journal-title":"Brain Res."},{"key":"2021112214594040700_B17","doi-asserted-by":"crossref","first-page":"44670","DOI":"10.1074\/jbc.M204379200","article-title":"Overexpression of Alzheimer's disease amyloid-\u03b2 opposes the age-dependent elevations of brain copper and iron","volume":"277","author":"Maynard","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B18","doi-asserted-by":"crossref","first-page":"14193","DOI":"10.1073\/pnas.2332851100","article-title":"In vivo reduction of amyloid-\u03b2 by a mutant copper transporter","volume":"100","author":"Phinney","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112214594040700_B19","doi-asserted-by":"crossref","first-page":"20378","DOI":"10.1074\/jbc.M400805200","article-title":"Copper depletion down-regulates expression of the Alzheimer's disease amyloid-\u03b2 precursor protein gene","volume":"279","author":"Bellingham","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B20","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1042\/bj3440461","article-title":"Copper inhibits \u03b2-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion","volume":"344","author":"Borchardt","year":"1999","journal-title":"Biochem. J."},{"key":"2021112214594040700_B21","first-page":"101","article-title":"Molecular biology of metal homeostasis and detoxification","volume-title":"Topics in Current Genetics","author":"Cater","year":"2005"},{"key":"2021112214594040700_B22","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1053\/j.gastro.2005.10.054","article-title":"ATP7B mediates vesicular sequestration of copper; insight into biliary copper excretion","volume":"130","author":"Cater","year":"2006","journal-title":"Gastroenterology"},{"key":"2021112214594040700_B23","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1152\/ajpgi.00472.2006","article-title":"Dynamics of endogenous ATP7A (Menkes protein) in intestinal epithelial cells: copper-dependent redistribution between two intracellular sites","volume":"292","author":"Nyasae","year":"2006","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"2021112214594040700_B24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1523\/JNEUROSCI.3699-04.2005","article-title":"NMDA receptor activation mediates copper homeostasis in hippocampal neurons","volume":"25","author":"Schlief","year":"2005","journal-title":"J. Neurosci."},{"key":"2021112214594040700_B25","doi-asserted-by":"crossref","first-page":"14187","DOI":"10.1073\/pnas.2332818100","article-title":"Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid A\u03b2 production in APP23 transgenic mice","volume":"100","author":"Bayer","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112214594040700_B26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0022-510X(96)00203-1","article-title":"Copper, iron and zinc imbalances in severely degenerative brain regions in Alzheimer's disease: possible relation to oxidative stress","volume":"143","author":"Deibel","year":"1996","journal-title":"J. Neurol. Sci."},{"key":"2021112214594040700_B27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0006-8993(96)00782-2","article-title":"Increased regional brain concentrations of ceruloplasmin in neurodegenerative disorders","volume":"738","author":"Loeffler","year":"1996","journal-title":"Brain Res."},{"key":"2021112214594040700_B28","first-page":"241","article-title":"Trace elements in Alzheimer's disease brain: A new hypothesis","volume":"2","author":"Rao","year":"1999","journal-title":"Alzheimers Rep."},{"key":"2021112214594040700_B29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1212\/01.wnl.0000223644.08653.b5","article-title":"Elevated cortical zinc in Alzheimer disease","volume":"67","author":"Religa","year":"2006","journal-title":"Neurology"},{"key":"2021112214594040700_B30","doi-asserted-by":"crossref","first-page":"31375","DOI":"10.1074\/jbc.273.47.31375","article-title":"Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases","volume":"273","author":"La\u00a0Fontaine","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B31","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1042\/bj20031804","article-title":"Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal binding sites","volume":"380","author":"Cater","year":"2004","journal-title":"Biochem. J."},{"key":"2021112214594040700_B32","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1152\/ajpregu.00806.2005","article-title":"Alteration of copper physiology in mice overexpressing the human Menkes protein ATP7A","volume":"290","author":"Ke","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"2021112214594040700_B33","doi-asserted-by":"crossref","first-page":"22908","DOI":"10.1074\/jbc.271.37.22908","article-title":"Analysis of heterogeneous \u03b2A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay","volume":"271","author":"Ida","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B34","doi-asserted-by":"crossref","first-page":"6207","DOI":"10.1523\/JNEUROSCI.18-16-06207.1998","article-title":"Survival of cultured neurons from amyloid precursor protein knock-out mice against Alzheimer's amyloid-toxicity and oxidative stress","volume":"18","author":"White","year":"1998","journal-title":"J. Neurosci."},{"key":"2021112214594040700_B35","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/0092-8674(89)90177-3","article-title":"Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein","volume":"57","author":"Weidemann","year":"1989","journal-title":"Cell"},{"key":"2021112214594040700_B36","doi-asserted-by":"crossref","first-page":"17670","DOI":"10.1074\/jbc.M602487200","article-title":"Degradation of the Alzheimer disease amyloid \u03b2-peptide by metal-dependent up-regulation of metalloprotease activity","volume":"281","author":"White","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B37","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1474-9726.2006.00200.x","article-title":"Overexpression of A\u03b2 is associated with acceleration of onset of motor impairment and superoxide dismutase 1 aggregation in amyotrophic lateral sclerosis mouse models","volume":"5","author":"Li","year":"2006","journal-title":"Aging Cell"},{"key":"2021112214594040700_B38","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.1002\/j.1460-2075.1996.tb00997.x","article-title":"Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking","volume":"15","author":"Petris","year":"1996","journal-title":"EMBO J."},{"key":"2021112214594040700_B39","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1046\/j.1471-4159.2001.00012.x","article-title":"Functional \u03b3-secretase inhibitors reduce \u03b2-amyloid peptide levels in brain","volume":"76","author":"Dovey","year":"2001","journal-title":"J. Neurochem."},{"key":"2021112214594040700_B40","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1093\/embo-reports\/kve180","article-title":"Presenilin-dependent \u03b3-secretase processing of \u03b2-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch","volume":"2","author":"Sastre","year":"2001","journal-title":"EMBO Rep."},{"key":"2021112214594040700_B41","doi-asserted-by":"crossref","first-page":"2823","DOI":"10.1038\/sj.emboj.7601735","article-title":"Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin","volume":"26","author":"De\u00a0Domenico","year":"2007","journal-title":"EMBO J."},{"key":"2021112214594040700_B42","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1212\/WNL.57.2.260","article-title":"Mitochondrial enzyme-deficient hippocampal neurons and choroidial cells in AD","volume":"57","author":"Cottrell","year":"2001","journal-title":"Neurology"},{"key":"2021112214594040700_B43","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S0197-4580(00)00112-3","article-title":"A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients","volume":"21","author":"Maurer","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"2021112214594040700_B44","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.pnpbp.2004.12.007","article-title":"Mitochondrial aging and dysfunction in Alzheimer's disease","volume":"29","author":"Sullivan","year":"2005","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"2021112214594040700_B45","first-page":"9","article-title":"Superoxide dismutase activity in cerebrospinal fluid of patients with dementia and some other neurological disorders","volume":"12","author":"De\u00a0Deyn","year":"1998","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"2021112214594040700_B46","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3233\/JAD-1999-1301","article-title":"Increased expression but reduced activity of antioxidant enzymes in Alzheimer's disease","volume":"1","author":"Omar","year":"1999","journal-title":"J. Alzheimers Dis."},{"key":"2021112214594040700_B47","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1126\/science.286.5440.735","article-title":"\u03b2-Secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE","volume":"286","author":"Vassar","year":"1999","journal-title":"Science"},{"key":"2021112214594040700_B48","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/990107","article-title":"Membrane-anchored aspartyl protease with Alzheimer's disease activity","volume":"402","author":"Yan","year":"1999","journal-title":"Nature"},{"key":"2021112214594040700_B49","doi-asserted-by":"crossref","first-page":"17930","DOI":"10.1074\/jbc.M412034200","article-title":"BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper","volume":"280","author":"Angeletti","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B50","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.mcn.2003.12.013","article-title":"BACE (\u03b2-secretase) modulates the processing of APLP2 in vivo","volume":"25","author":"Pastorino","year":"2004","journal-title":"Mol. Cell. Neurosci."},{"key":"2021112214594040700_B51","doi-asserted-by":"crossref","first-page":"44194","DOI":"10.1074\/jbc.M208110200","article-title":"Processing of \u03b2-amyloid precursor-like protein-1 and -2 by \u03b3-secretase regulates transcription","volume":"277","author":"Scheinfeld","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021112214594040700_B52","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.biopsych.2005.09.007","article-title":"Toward a reliable distinction between patients with mild cognitive impairment and Alzheimer-type dementia versus major depression","volume":"59","author":"Post","year":"2006","journal-title":"Biol. Psychiatry."},{"key":"2021112214594040700_B53","doi-asserted-by":"crossref","first-page":"11065","DOI":"10.1073\/pnas.1832769100","article-title":"Trace amounts of copper in water induce \u03b2-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease","volume":"100","author":"Sparks","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112214594040700_B54","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1172\/JCI23610","article-title":"Alzheimer disease \u03b2-amyloid activity mimics cholesterol oxidase","volume":"115","author":"Puglielli","year":"2005","journal-title":"Clin. Invest."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/412\/1\/141\/651498\/bj4120141.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/412\/1\/141\/651498\/bj4120141.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,22]],"date-time":"2021-11-22T19:45:24Z","timestamp":1637610324000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/412\/1\/141\/44317\/Intracellular-copper-deficiency-increases-amyloid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,4,25]]},"references-count":54,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2008,5,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20080103","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,4,25]]}}}