Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons.
Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes' and Wilson's diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases, Parkinson's disease and amyotrophic lateral sclerosis. It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1alpha, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons.
Spisni
Enzo
E
Department of Experimental Biology, University of Bologna, Bologna, Italy. enzo.spisni@unibo.it
Valerii
Maria Chiara
MC
Manerba
Marcella
M
Strillacci
Antonio
A
Polazzi
Elisabetta
E
Mattia
Toni
T
Griffoni
Cristiana
C
Tomasi
Vittorio
V
D000209:Acute-Phase Proteins / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000737:chemistry; D021984:Cyclophilin A / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D015676:Osteonectin / Q000378:metabolism; D010449:Peptide Mapping; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013054:Spectrophotometry, Atomic; D014131:Trace Elements / Q000378:metabolism* / Q000494:pharmacology*
D000209:Acute-Phase Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D015676:Osteonectin; D011518:Proto-Oncogene Proteins; D014131:Trace Elements; D003300:Copper; D021984:Cyclophilin A