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Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione (1999)

White, Anthony R. ; Bush, Ashley I. ; Beyreuther, Konrad ; [et al.]

Oxford, UK : Blackwell Publishing Ltd

Journal of neurochemistry 72 (1999), S. 0

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ISSN: 1471-4159

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: Abstract: 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-β (Aβ) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Aβ25-35 in the presence or absence of Cu or Fe. Aβ25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Aβ to perturb neuronal GSH homeostasis. Aβ25-35 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.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0722092.x

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A synthetic substrate assay for the gamma-secretase of the β-A4 amyloid of alzheimer's disease (1995)

Evin, Geneviève ; Beyreuther, Konrad ; Masters, Colin L.

New York, NY [u.a.] : Wiley-Blackwell

Journal of Peptide Science 1 (1995), S. 132-139

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ISSN: 1075-2617

Keywords: βA4 amyloid peptide ; radiometric assay ; transmembrane peptide ; reverse-phase TLC ; Chemistry ; Biochemistry and Biotechnology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: γ-secretase, the endoprotease which releases the C-terminus of βA4 amyloid peptide, cleaves within the hydrophobic transmembrane domain of the amyloid precursor protein. In order to obtain a substrate for γ-secretase, a dodecapeptide which spans the cleavage site was synthesized, labelled with 125-iodine and conjugated to an agarose gel. A radiometric solid-phase assay was developed using this immobilized substrate. Peptide products were separated by reverse-phase HPLC and TLC to allow characterization of the cleavage site(s).

Additional Material: 4 Ill.