Metal chelator decreases Alzheimer beta-amyloid plaques.
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Transgenic mice developing beta-amyloid (Abeta) plaques are advancing experimental treatment strategies for Alzheimer's disease. The metal chelator, clioquinol, is reported by Cherny et al. (2001) to reduce Abeta plaques, presumably by chelation of Abeta-associated zinc and copper. This and other recent Abeta-modulating treatment approaches are discussed. (+info)
Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.
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Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.0001) in a blinded study of APP2576 transgenic mice treated orally for 9 weeks with clioquinol, an antibiotic and bioavailable Cu/Zn chelator. This was accompanied by a modest increase in soluble Abeta (1.45% of total cerebral Abeta); APP, synaptophysin, and GFAP levels were unaffected. General health and body weight parameters were significantly more stable in the treated animals. These results support targeting the interactions of Cu and Zn with Abeta as a novel therapy for the prevention and treatment of AD. (+info)
An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript.
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Iron-responsive elements (IREs) are the RNA stem loops that control cellular iron homeostasis by regulating ferritin translation and transferrin receptor mRNA stability. We mapped a novel iron-responsive element (IRE-Type II) within the 5'-untranslated region (5'-UTR) of the Alzheimer's amyloid precursor protein (APP) transcript (+51 to +94 from the 5'-cap site). The APP mRNA IRE is located immediately upstream of an interleukin-1 responsive acute box domain (+101 to +146). APP 5'-UTR conferred translation was selectively down-regulated in response to intracellular iron chelation using three separate reporter assays (chloramphenicol acetyltransferase, luciferase, and red fluorescent protein reflecting an inhibition of APP holoprotein translation in response to iron chelation. Iron influx reversed this inhibition. As an internal control to ensure specificity, a viral internal ribosome entry sequence was unresponsive to intracellular iron chelation with desferrioxamine. Using RNA mobility shift assays, the APP 5'-UTRs, encompassing the IRE, bind specifically to recombinant iron-regulatory proteins (IRP) and to IRP from neuroblastoma cell lysates. IRP binding to the APP 5'-UTR is reduced after treatment of cells with desferrioxamine and increased after interleukin-1 stimulation. IRP binding is abrogated when APP cRNA probe is mutated in the core IRE domain (Delta4 bases:Delta83AGAG86). Iron regulation of APP mRNA through the APP 5'-UTR points to a role for iron in the metabolism of APP and confirms that this RNA structure can be a target for the selection of small molecule drugs, such as desferrioxamine (Fe chelator) and clioquinol (Fe, Cu, and Zn chelator), which reduce Abeta peptide burden during Alzheimer's disease. (+info)
Ironic fate: can a banned drug control metal heavies in neurodegenerative diseases?
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In this issue of Neuron, Kaur et al. demonstrate that iron chelation by ferritin transgene or the metal chelator clioquinol prevent oxidative damage and MPTP toxicity in mice. This raises the issue of specific iron chelators or clioquinol for control of oxidative damage in Parkinson's, Alzheimer's, and other neurodegenerative diseases, but not without safety concerns. (+info)
Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease.
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Studies on postmortem brains from Parkinson's patients reveal elevated iron in the substantia nigra (SN). Selective cell death in this brain region is associated with oxidative stress, which may be exacerbated by the presence of excess iron. Whether iron plays a causative role in cell death, however, is controversial. Here, we explore the effects of iron chelation via either transgenic expression of the iron binding protein ferritin or oral administration of the bioavailable metal chelator clioquinol (CQ) on susceptibility to the Parkinson's-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP). Reduction in reactive iron by either genetic or pharmacological means was found to be well tolerated in animals in our studies and to result in protection against the toxin, suggesting that iron chelation may be an effective therapy for prevention and treatment of the disease. (+info)
Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis.
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Between about 1955 and 1970, some 100,000 Japanese were diagnosed as having subacute myelooptic neuropathy (SMON), a new disease characterized by abdominal and neurological manifestations, the former nearly always preceding the latter. Circumstantial evidence obtained in 1969-70 suggested that SMON might have been caused by clioquinol (CQL), a gastrointestinal disinfectant, and led to the suspension of further sales of CQL in Japan. However, several inconsistencies for the CQL theory of SMON have now emerged; first, CQL had been widely used in Japan for nearly 20 years before SMON occurred. Secondly, the SMON epidemic began to subside several months before CQL sales were suspended. Thirdly, a large proportion of SMON patients--probably about one-third and possibly more--had not taken CQL within six months of the onset of the disease (the modal interval between first taking CQL and the onset of SMON being about three weeks, and more than 100 days in only 4% of SMON patients); of the remaining two-thirds or so, many had taken CQL as part of the treatment of the first (that is, abdominal) symptoms of SMON itself. Fourthly, there was no dose-response relationship. Finally, SMON rarely, if ever, occurred outside Japan. CQL could, however, have been involved in the causation of SMON as an optional enhancer of some other necessary cause; the history of post-war environmental pollution in Japan is compatible with this hypothesis. Over-readiness to accept postulated toxic effects of medicines and chemicals as proven is likely to do at least as much harm as good to individual and community health. (+info)
Cu2+-induced modification of the kinetics of A beta(1-42) channels.
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We found that the amyloid beta peptide A beta(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu2+ or biological redox agents that have been reported to mediate A beta(1-42) toxicity. The A beta(1-42)-formed cation channel was inhibited by Cu2+ in cis solution ([Cu2+]cis) in a voltage- and concentration-dependent manner between 0 and 250 microM. The [Cu2+]cis-induced channel inhibition is fully reversible at low concentrations between 50 and 100 microM [Cu2+]cis and partially reversible at 250 microM [Cu2+]cis. The inhibitory effects of [Cu2+]cis between 50 and 250 microM on the channel could not be reversed with addition of Cu2+-chelating agent clioquinol (CQ) at concentrations between 64 and 384 microM applied to the cis chamber. The effects of 200-250 microM [Cu2+]cis on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 microM [CQ]cis. The kinetic analysis of the data indicate that Cu2+-induced inhibition was mediated via both desensitization and an open channel block mechanism and that Cu2+ binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu2+-binding site of the A beta(1-42)-formed channels is modulated with Cu2+ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu2+ modulation of A beta and PrP channel proteins linked to neurodegenerative diseases. (+info)
Changes in intracellular calcium and glutathione in astrocytes as the primary mechanism of amyloid neurotoxicity.
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Although the accumulation of the neurotoxic peptide beta amyloid (betaA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of betaA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide betaA (1-42) and the neurotoxic fragment (25-35) caused sporadic cytoplasmic calcium [intracellular calcium ([Ca2+]c)] signals in astrocytes that continued for hours, whereas adjacent neurons were completely unaffected. Nevertheless, after 24 hr, although astrocyte cell death was marginally increased, approximately 50% of the neurons had died. The [Ca2+]c signal was entirely dependent on Ca2+ influx and was blocked by zinc and by clioquinol, a heavy-metal chelator that is neuroprotective in models of Alzheimer's disease. Neuronal death was associated with Ca2+-dependent glutathione depletion in both astrocytes and neurons. Thus, astrocytes appear to be the primary target of betaA, whereas the neurotoxicity reflects the neuronal dependence on astrocytes for antioxidant support. (+info)