Linked Life Data

18248325

Source:http://linkedlifedata.com/resource/pubmed/id/18248325

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-4-22
pubmed:abstractText
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 Abeta (amyloid beta-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 Abeta. Human fibroblasts genetically disposed to copper accumulation secreted higher levels of sAPP (soluble APP ectodomain)alpha into their medium, whereas fibroblasts genetically manipulated to be profoundly copper deficient secreted predominantly sAPPbeta and produced more amyloidogenic beta-cleaved APP C-termini (C99). The level of Abeta secreted from copper-deficient fibroblasts was however regulated and limited by alpha-secretase cleavage. APP can be processed by both alpha- and beta-secretase, as copper-deficient fibroblasts secreted sAPPbeta exclusively, but produced primarily alpha-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 Abeta secretion, but did not affect the cleavage of APP. Therefore copper deficiency markedly alters APP metabolism and can elevate Abeta 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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1470-8728
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
412
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
141-52
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:18248325-Amino Acid Sequence, pubmed-meshheading:18248325-Amyloid Precursor Protein Secretases, pubmed-meshheading:18248325-Amyloid beta-Peptides, pubmed-meshheading:18248325-Amyloid beta-Protein Precursor, pubmed-meshheading:18248325-Cells, Cultured, pubmed-meshheading:18248325-Copper, pubmed-meshheading:18248325-Fibroblasts, pubmed-meshheading:18248325-Gene Expression Regulation, pubmed-meshheading:18248325-Humans, pubmed-meshheading:18248325-Intracellular Fluid, pubmed-meshheading:18248325-Molecular Sequence Data, pubmed-meshheading:18248325-Nerve Tissue Proteins, pubmed-meshheading:18248325-Neurons, pubmed-meshheading:18248325-Protein Biosynthesis, pubmed-meshheading:18248325-Protein Processing, Post-Translational, pubmed-meshheading:18248325-Sequence Homology, Amino Acid, pubmed-meshheading:18248325-Signal Transduction, pubmed-meshheading:18248325-Transcription, Genetic
pubmed:year
2008
pubmed:articleTitle
Intracellular copper deficiency increases amyloid-beta secretion by diverse mechanisms.
pubmed:affiliation
Oxidation Biology Laboratory, Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't