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• W2112633282 endingPage "9179" @default.
• W2112633282 startingPage "9170" @default.
• W2112633282 abstract "The amyloid precursor protein (APP) of Alzheimer's disease can reduce copper (II) to copper (I) in a cell-free system potentially leading to increased oxidative stress in neurons. We used neuronal cultures derived from APP knock-out (APP −/− ) and wild-type (WT) mice to examine the role of APP in copper neurotoxicity. WT cortical, cerebellar, and hippocampal neurons were significantly more susceptible than their respective APP −/− neurons to toxicity induced by physiological concentrations of copper but not by zinc or iron. There was no difference in copper toxicity between APLP2 −/− and WT neurons, demonstrating specificity for APP-associated copper toxicity. Copper uptake was the same in WT and APP −/− neurons, suggesting APP may interact with copper to induce a localized increase in oxidative stress through copper (I) production. This was supported by significantly higher levels of copper-induced lipid peroxidation in WT neurons. Treatment of neuronal cultures with a peptide corresponding to the human APP copper-binding domain (APP142–166) potentiated copper but not iron or zinc toxicity. Incubation of APP142–166 with low-density lipoprotein (LDL) and copper resulted in significantly increased lipid peroxidation compared to copper and LDL alone. Substitution of the copper coordinating histidine residues with asparagines (APP142–166 H147N, H149N, H151N ) abrogated the toxic effects. A peptide corresponding to the zinc-binding domain (APP181–208) failed to induce copper or zinc toxicity in neuronal cultures. These data support a role for the APP copper-binding domain in APP-mediated copper (I) generation and toxicity in primary neurons, a process that has important implications for Alzheimer's disease and other neurodegenerative disorders." @default.
• W2112633282 created "2016-06-24" @default.
• W2112633282 creator A5033891416 @default.
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• W2112633282 date "1999-11-01" @default.
• W2112633282 modified "2023-09-24" @default.
• W2112633282 title "The Alzheimer's Disease Amyloid Precursor Protein Modulates Copper-Induced Toxicity and Oxidative Stress in Primary Neuronal Cultures" @default.
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• W2112633282 doi "https://doi.org/10.1523/jneurosci.19-21-09170.1999" @default.
• W2112633282 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6782934" @default.
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• W2112633282 hasPublicationYear "1999" @default.
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