In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 19, No. 21 ( 1999-11-01), p. 9170-9179
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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.19-21-09170.1999
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
1999
detail.hit.zdb_id:
1475274-8
SSG:
12
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