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The Journal of Neuroscience, November 1, 1999, 19(21):9170-9179
The Alzheimer's Disease Amyloid Precursor Protein Modulates
Copper-Induced Toxicity and Oxidative Stress in Primary Neuronal
Cultures
Anthony R.
White1, 2,
Gerd
Multhaup3,
Fran
Maher1, 2,
Shayne
Bellingham4,
James
Camakaris4,
Hui
Zheng5,
Ashley I.
Bush1, 2, 6,
Konrad
Beyreuther3,
Colin L.
Masters1, 2, and
Roberto
Cappai1, 2
1 Department of Pathology, The University of Melbourne,
Parkville, 3052 Victoria, Australia, 2 The Mental Health
Research Institute, Parkville, 3052 Victoria, Australia,
3 Center for Molecular Biology, The University of
Heidelberg, 69120 Heidelberg, Germany, 4 Department of
Genetics, The University of Melbourne, Parkville, 3052 Victoria,
Australia, 5 Department of Genetics and Molecular Biology,
Merck Research Laboratories, Rahway, New Jersey 07065, and
6 Department of Psychiatry, and Genetics and Aging Unit,
Harvard Medical School, Massachusetts General Hospital,
Charlestown, Massachusetts 02129
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
(APP142-166H147N, 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.
Key words:
Alzheimer's; copper; free radicals; culture; knock-out; lipid peroxidation; neurons
Copyright © 1999 Society for Neuroscience 0270-6474/99/19219170-10$05.00/0
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