Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease

Freie Universitaet Berlin, Institut fuer Chemie/Biochemie, Thielallee 63, D-14195 Berlin, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2005; 279(50):51958-64. DOI: 10.1074/jbc.M407410200
Source: PubMed


The key protein in Alzheimer's disease, the amyloid precursor protein (APP), is a ubiquitously expressed copper-binding glycoprotein that gives rise to the Abeta amyloid peptide. Whereas overexpression of APP results in significantly reduced brain copper levels in three different lines of transgenic mice, knock-out animals revealed increased copper levels. A provoked rise in peripheral levels of copper reduced concentrations of soluble amyloid peptides and resulted in fewer pathogenic Abeta plaques. Contradictory evidence has been provided by the efficacy of copper chelation treatment with the drug clioquinol. Using a yeast model system, we show that adding clioquinol to the yeast culture medium drastically increased the intracellular copper concentration but there was no significant effect observed on zinc levels. This finding suggests that clioquinol can act therapeutically by changing the distribution of copper or facilitating copper uptake rather than by decreasing copper levels. The overexpression of the human APP or APLP2 extracellular domains but not the extracellular domain of APLP1 decreased intracellular copper levels. The expression of a mutant APP deficient for copper binding increased intracellular copper levels several-fold. These data uncover a novel biological function for APP and APLP2 in copper efflux and provide a new conceptual framework for the formerly diverging theories of copper supplementation and chelation in the treatment of Alzheimer's disease.

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    • "derivative, namely the PBT2, has successfully completed early phase clinical trials and shown very interesting properties in AD,[127] that were partially attributed to Cu(II) transfer into the intra-cellular compartment.[128] [129] [130] Affinity for Cu(II) is moderate and depends on the stoichiometry of the complex formed (Table 1). "
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    ABSTRACT: Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and Heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies.
    Current topics in medicinal chemistry 01/2013; 12(22). DOI:10.2174/1568026611212220011 · 3.40 Impact Factor
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    • "Furthermore, APP plays a role in regulation of cellular copper export. Several studies have shown that over-expression of APP leads to decreased copper in yeast (Treiber et al., 2004) and in brains of mice (Maynard et al., 2002). That copper metabolism is involved in the pathogenesis of Alzheimer’s disease is however, emphasized as several polymorphisms in the gene encoding the copper transporter ATP7B seem to be linked to the development of Alzheimer’s disease. "
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    ABSTRACT: Iron and copper are important co-factors for a number of enzymes in the brain, including enzymes involved in neurotransmitter synthesis and myelin formation. Both shortage and an excess of iron or copper will affect the brain. The transport of iron and copper into the brain from the circulation is strictly regulated, and concordantly protective barriers, i.e., the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCB) have evolved to separate the brain environment from the circulation. The uptake mechanisms of the two metals interact. Both iron deficiency and overload lead to altered copper homeostasis in the brain. Similarly, changes in dietary copper affect the brain iron homeostasis. Moreover, the uptake routes of iron and copper overlap each other which affect the interplay between the concentrations of the two metals in the brain. The divalent metal transporter-1 (DMT1) is involved in the uptake of both iron and copper. Furthermore, copper is an essential co-factor in numerous proteins that are vital for iron homeostasis and affects the binding of iron-response proteins to iron-response elements in the mRNA of the transferrin receptor, DMT1, and ferroportin, all highly involved in iron transport. Iron and copper are mainly taken up at the BBB, but the BCB also plays a vital role in the homeostasis of the two metals, in terms of sequestering, uptake, and efflux of iron and copper from the brain. Inside the brain, iron and copper are taken up by neurons and glia cells that express various transporters.
    Frontiers in Pharmacology 09/2012; 3:169. DOI:10.3389/fphar.2012.00169 · 3.80 Impact Factor
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    • "However, while it cannot be excluded that the ability of DFO to chelate metals may have had a role in the protective effects observed in our study, chelation is involved in the formation of a metal complex that cannot readily cross the blood– brain barrier (Crowe and Morgan, 1994). It is interesting that clioquinol was found to attenuate APP/A␤ pathology by mediating the redistribution of copper (by facilitating copper uptake into the cell), rather than by removing copper from the system (Cherny et al., 2001; Treiber et al., 2004). As an aside, it is not surprising that intranasal treatment of DFO normalized serum Fe concentration , given that DFO is rapidly delivered to the brain along the olfactory and trigeminal nerves with negligible adverse systemic side effects. "
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    ABSTRACT: Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-β (Aβ)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on Aβ neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl(3)) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the Aβ burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease.
    Neurobiology of aging 06/2012; 34(2). DOI:10.1016/j.neurobiolaging.2012.05.009 · 5.01 Impact Factor
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