Exacerbation of copper toxicity in primary neuronal cultures depleted of cellular glutathione.
Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-1-nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-beta (Abeta) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Abeta25-35 in the presence or absence of Cu or Fe. Abeta25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Abeta to perturb neuronal GSH homeostasis. Abeta25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.
White
A R
AR
Department of Pathology, University of Melbourne, and Mental Health Research Institute, Victoria, Australia.
Bush
A I
AI
Beyreuther
K
K
Masters
C L
CL
Cappai
R
R
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D003300:Copper / Q000037:antagonists & inhibitors / Q000506:poisoning*; D004338:Drug Combinations; D004357:Drug Synergism; D016166:Free Radical Scavengers / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D004338:Drug Combinations; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D019328:Buthionine Sulfoximine; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D003300:Copper; D005980:Glutathione Reductase; D005978:Glutathione