Amyloid precursor protein, copper and Alzheimer's disease

doi:10.1016/S0753-3322(97)86907-7

Biomedicine & Pharmacotherapy

Volume 51, Issue 3, 1997, Pages 105-111

https://doi.org/10.1016/S0753-3322(97)86907-7 Get rights and content

Summary

Although a consensus that Alzheimer's disease (AD) is a single disease has not yet been reached, the involvement of the amyloid precursor protein (APP) and βA4 (Aβ) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of βA4 in cell cultures, and the findings that aggregation of βA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals might be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS might be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.

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The many data indicating that the natural APP/Aβ function relates to copper (and possibly zinc) transport at the synapses put the amyloid hypothesis in close and logic relationship to the model described above. Since the APP/Aβ system aids copper transport at the synapses, the disruption of Aβ levels by PSEN or APP mutations would contribute to a disturbance of the copper homeostasis, as indicated in Fig. 3B [60,277,396]. In this model, APP and PSEN mutations, the main genetic risk factors of familial early-onset AD, cause disease by a partial loss of function that manifests at high age when the overall copper homeostasis is already stressed.
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This should be taken into consideration especially when evaluating the toxicity of environmental pollutants found at currently-considered non- or sub-toxic concentrations, as they could exercise a synergistic action or manifest an unexpected level of toxicity. The present results could become of special relevance in cases where elevated levels of copper occur either in body fluids or in cells (Chevion et al., 1993; Multhaup, 1997; Ogihara et al., 1995; Shubber et al., 1998; Tanner, 1998), such as in patients who suffer from Wilson's Disease (Ogihara et al., 1995) and in people who use copper-containing intrauterine contraceptive devices (Shubber et al., 1998). The better understanding of the role of transition metals and free radicals in PCP and other PCP-induced cytotoxicities could lead to the reevaluation of the effects they imposed to the human health.
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The large number of patients suffering from neurodegenerative diseases like Alzheimer's disease and Parkinson's disease motivates many research groups worldwide to investigate pathogenic factors and molecular mechanisms of these diseases. Recent studies and reviews indicate that metals are involved in these neurodegenerative processes in case their homeostasis in the brain is disturbed. Important is that the focus of these recent studies is on essential metals like Fe, Cu, Zn and Mn, but not on the well-known neurotoxic metals like Hg and Pb. Key issues for understanding metal induced neurotoxic effects are the transport processes across the neural barriers, the metal binding forms (species) and their interactions with neuronal structures. Total metal concentrations in cerebrospinal fluid were published in several studies for controls and patients, but the amount of reliable data sets is not yet sufficient for clear definition of normal and elevated levels.
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Amyloid precursor protein, copper and Alzheimer's disease

Summary

J Biol Chem

Lancet

J Biol Chem

Cell

Neuron

J Biol Chem

Brain Res

Trends Neurosci

Neuron

J Biol Chem

J Biol Chem

Biochimie

FEBS Lett

Thromb Res

Thromb Res

FEBS Let

Methods Enzymol

J Biol Chem

Arch Biochem Biophys

FEBS Lett

Free Radic Biol Med

J Biol Chem

J Biol Chem

Cell

Neuron

J Biol Chem

FEBS Lett

FEBS Lett

Neuroscience

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease

Nature Med

Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene

Nature

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease

Nature

Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β-amyloid precursor protein gene

Nat Genet

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of β-amyloid

Nat Genet

Cloning of a gene bearing missense muations in early-onset familial Alzheimer's disease

Nature

Nucleotide sequence of the chromosome 14-encoded S182 cDNA and revised secondary structure prediction. Amyloid

Int J Exp Clin Invest