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13 - Copper and zinc in Alzheimer's disease and amyotrophic lateral sclerosis

from Part I - Basic aspects of neurodegeneration

Published online by Cambridge University Press:  04 August 2010

M. Flint Beal ,
Anthony E. Lang  and
Albert C. Ludolph
By
Avi L. Friedlich  and
Ashley I. Bush
M. Flint Beal
Affiliation:
Cornell University, New York
Anthony E. Lang
Affiliation:
University of Toronto
Albert C. Ludolph
Affiliation:
Universität Ulm, Germany
Avi L. Friedlich
Affiliation:
Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, MA, USA
Ashley I. Bush
Affiliation:
Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, MA, USA
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Summary

Introduction

The non-infectious neurodegenerative disorders, Alzheimer's disease, and amyotrophic lateral sclerosis are heterogeneous with respect to etiology, neuropathology and clinical presentation. Yet, these disorders share a number of features in common to suggest some common pathogenic events. Each disorder is age related and is characterized by progressive and symmetric degeneration of discrete populations of neurons. Each disorder is associated with biochemical markers of oxidative attack, and each is associated with deposition of a CuZn metalloprotein in affected tissue.

Molecular genetic analysis has linked autosomal dominant forms of AD, PD, and amyotrophic lateral sclerosis, respectively, to mutations in ß-amyloid precursor protein, α-synuclein, and superoxide dismutase 1. Each of these proteins or its proteolytic products may aggregate in affected tissue during the course of disease.

In this chapter we summarize current knowledge of CNS Cu and Zn metabolism in normal physiology. Then, focusing on AD and ALS, we review evidence for pathophysiologic Cu and Zn metabolism and evidence linking Cu and Zn to the physiologic and toxic activities of ß-amyloid protein and superoxide dismutase 1.

Protein interactions in brain copper and zinc metabolism

At the active site of many enzymes, Cu participates in one-electron transfer reactions. Zn, which is electrochemically inert, maintains structural stability of many proteins. In addition to these essential and ubiquitous roles for Cu and Zn, brain-specific functions exist for these metals.

Type
Chapter
Information
Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
 , pp. 157 - 165
Publisher: Cambridge University Press
Print publication year: 2005

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References

Andrus, P. K., Fleck, T. J., Gurney, M. E. & Hall, E. D. (1998). Protein oxidative damage in a transgenic mouse model of familial amyotrophic lateral sclerosis.J. Neurochem., 71(5), 2041–8CrossRefGoogle Scholar
Asahina, M., Yoshiyama, Y. & Hattori, T. (2001). Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer's disease brain.Clin. Neuropathol., 20(2): 60–3Google ScholarPubMed
Assaf, S. Y. & Chung, S.-H. (1984). Release of endogenous Zn2+ from brain tissue during activity.Nature, 308, 734–6CrossRefGoogle ScholarPubMed
Atwood, C. S., Moir, R. D., Huang, X.et al. (1998). Dramatic aggregation of Alzheimer Aß by Cu(II) is induced by conditions representing physiological acidosis.J. Biol. Chem., 273, 12817–26CrossRefGoogle Scholar
Atwood, C. S., Huang, X., Moir, R. D., Tanzi, R. E. & Bush, A. I. (1999). Role of free radicals and metal ions in the pathogenesis of Alzheimer's disease.Met. Ions Biol. Syst., 36, 309–64Google ScholarPubMed
Atwood, C. S., Scarpa, R. C., Huang, X.et al. (2000). Characterization of copper interactions with Alzheimer Aß peptides – identification of an attomolar affinity copper binding site on Aß1-42.J. Neurochem., 75, 1219–33CrossRefGoogle Scholar
Backstrom, J. R., Miller, C. A. & Tokes, Z. A. (1992). Characterization of neutral proteinases from Alzheimer-affected and control brain specimens: identification of calcium-dependent metalloproteinases from the hippocampus.J. Neurochem., 58(3), 983–92CrossRefGoogle ScholarPubMed
Basun, H., Forssell, L. G., Wetterberg, L. & Winblad, B. (1991). Metals and trace elements in plasma and cerebrospinal fluid in normal aging and Alzheimer's disease.J. Neural. Transm. Park. Dis. Dement. Sect., 3(4), 231–58Google ScholarPubMed
Beal, M. F., Ferrante, R. J., Browne, S. E., Matthews, R. T., Kowall, N. W. & Brown, R. H. Jr. (1997). Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis.Ann. Neurol., 42(4), 644–54CrossRefGoogle ScholarPubMed
Blacker, D., Wilcox, M. A., Laird, N. M.et al. (1998). Alpha-2 macroglobulin is genetically associated with Alzheimer disease.Nat. Genet., 19(4), 357–60CrossRefGoogle ScholarPubMed
Brown, R. H. Jr. & Robberecht, W. (2001). Amyotrophic lateral sclerosis: pathogenesis.Semin. Neurol., 21(2), 131–9CrossRefGoogle ScholarPubMed
Bruijn, L. I., Beal, M. F., Becher, M. W.et al. (1997). Elevated free nitrotyrosine levels, but not protein-bound nitrotyrosine or hydroxyl radicals, throughout amyotrophic lateral sclerosis (ALS)-like disease implicate tyrosine nitration as an aberrant in vivo property of one familial ALS-linked superoxide dismutase 1 mutant.Proc. Natl. Acad. Sci., USA, 94(14), 7606–11CrossRefGoogle ScholarPubMed
Bruijn, L. I., Houseweart, M. K., Kato, S.et al. (1998). Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1.Science, 281(5384), 1851–4CrossRefGoogle ScholarPubMed
Bush, A. I. (2000). Metals and neuroscience.Curr. Opin. Chem. Biol., 4(2), 184–91CrossRefGoogle ScholarPubMed
Bush, A. I. (2002). Is ALS caused by an altered oxidative activity of mutant superoxide dismutase?Nat. Neurosci., 5(10), 919; author reply 919–20CrossRefGoogle ScholarPubMed
Bush, A. I., Pettingell, W. H., Multhaup, G.et al. (1994). Rapid induction of Alzheimer Aß amyloid formation by zinc.Science, 265, 1464–7CrossRefGoogle Scholar
Castellani, R. J., Smith, M. A., Nunomura, A., Harris, P. L. & Perry, G. (1999). Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?Free Radic. Biol. Med., 26(11–12), 1508–12CrossRefGoogle ScholarPubMed
Chelly, J., Tumer, Z., Tonnesen, T.et al. (1993). Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.Nat. Genet., 3(1), 14–19CrossRefGoogle ScholarPubMed
Cherny, R. A., Legg, J. T., McLean, C. A.et al. (1999). Aqueous dissolution of Alzheimer's disease Aß amyloid deposits by biometal depletion.J. Biol. Chem., 274, 23223–8CrossRefGoogle Scholar
Cherny, R. A., Atwood, C. S., Xilinas, M. E.et al. (2001). Treatment with a copper–zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.Neuron, 30(3), 665–76CrossRefGoogle ScholarPubMed
Cole, T. B., Wenzel, H. J., Kafer, K. E., Schwartzkroin, P. A. & Palmiter, R. D. (1999). Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc. Natl Acad. Sci., USA, 96, 1716–21CrossRefGoogle ScholarPubMed
Corrigan, F. M., Reynolds, G. P. & Ward, N. I. (1993). Hippocampal tin, aluminum and zinc in Alzheimer's disease.Biometals, 6, 149–54CrossRefGoogle ScholarPubMed
Crow, J. P., Sampson, J. B., Zhuang, Y., Thompson, J. A. & Beckman, J. S. (1997). Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite.J. Neurochem., 69(5), 1936–44CrossRefGoogle ScholarPubMed
Cuajungco, M. P., Goldstein, L. E., Nunomura, A.et al. (2000). Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of abeta by zinc.J. Biol. Chem., 275(26), 19439–42CrossRefGoogle ScholarPubMed
Curtain, C. C., Ali, F., Volitakis, I.et al. (2001). Alzheimer's disease amyloid-binds Cu and Zn to generate an allosterically-ordered membrane-penetrating structure containing SOD-like subunits. J. Biol. Chem., 276(23), 20466–73CrossRefGoogle Scholar
Danscher, G., Jensen, K. B., Frederickson, C. J.et al. (1997). Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material.J. Neurosci. Method., 76(1), 53–9CrossRefGoogle ScholarPubMed
Deibel, M. A., Ehmann, W. D. & Markesbery, W. R. (1996). Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress.J. Neurol. Sci., 143, 137–42CrossRefGoogle ScholarPubMed
Dong, J., Atwood, C. S., Anderson, V. E.et al. (2003). Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence.Biochemistry, 42(10), 2768–73CrossRefGoogle ScholarPubMed
Du, Y., Ni, B., Glinn, M.et al. (1997). alpha2-Macroglobulin as Aß-amyloid peptide-binding plasma protein.J. Neurochem., 69(1), 299–305CrossRefGoogle ScholarPubMed
Estevez, A. G., Crow, J. P., Sampson, J. B.et al. (1999). Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase.Science, 286(5449), 2498–500Google ScholarPubMed
Ferrante, R. J., Shinobu, L. A.Schulz, J. B.et al. (1997). Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation.Ann. Neurol., 42(3), 326–34CrossRefGoogle ScholarPubMed
Frederickson, C. J. (1989). Neurobiology of zinc and zinc-containing neurons.Int. Rev. Neurobiol., 31, 145–328CrossRefGoogle ScholarPubMed
Frederickson, C. J., Suh, S. W., Silva, D. & Thompson, R. B. (2000). Importance of zinc in the central nervous system: the zinc-containing neuron.J. Nutr., 130(5S Suppl), 1471S–83SCrossRefGoogle ScholarPubMed
Glenner, G. G. & Wong, C. W. (1984). Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem. Biophys Res. Commun., 120, 885–90CrossRefGoogle ScholarPubMed
Gong, Y. H. & Elliott, J. L. (2000). Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis.Exp. Neurol., 162(1), 27–36CrossRefGoogle Scholar
Goto, J. J., Zhu, H., Sanchez, R. J.et al. (2000). Loss of in vitro metal ion binding specificity in mutant copper-zinc superoxide dismutases associated with familial amyotrophic lateral sclerosis.J. Biol. Chem., 275(2), 1007–14CrossRefGoogle ScholarPubMed
Gurney, M. E., Liu, R., Althaus, J. S., Hall, E. D. & Becker, D. A. (1998). Mutant CuZn superoxide dismutase in motor neuron disease.J. Inherit. Metab. Dis., 21(5), 587–97CrossRefGoogle ScholarPubMed
Hambidge, M. & Krebs, N. F. (2001). Interrelationships of key variables of human zinc homeostasis: relevance to dietary zinc requirements.Annu. Rev. Nutr., 21, 429–52CrossRefGoogle ScholarPubMed
Hartter, D. E. & Barnea, A. (1988a). Brain tissue accumulates 67copper by two ligand-dependent saturable processes.J. Biol. Chem., 263, 799–805Google Scholar
Hartter, D. E. & Barnea, A. (1988b). Evidence for release of copper in the brain: depolarization-induced release of newly taken-up 67copper.Synapse, 2(4), 412–15CrossRefGoogle Scholar
Hershey, C. O., Hershey, L. A., Varnes, A., Vibhakar, S. D., Lavin, P. & Strain, W. H. (1983). Cerebrospinal fluid trace element content in dementia: clinical, radiologic, and pathologic correlations.Neurology, 33, 1350–3CrossRefGoogle ScholarPubMed
Howell, G. A., Welch, M. G. & Frederickson, C. J. (1984). Stimulation-induced uptake and release of zinc in hippocampal slices.Nature, 308, 736–8CrossRefGoogle ScholarPubMed
Hottinger, A. F., Fine, E. G., Gurney, M. E., Zurn, A. D. & Aebischer, P. (1997). The copper chelator d-penicillamine delays onset of disease and extends survival in a transgenic mouse model of familial amyotrophic lateral sclerosis.Eur. J. Neurosci., 9(7), 1548–51CrossRefGoogle Scholar
Huang, X., Atwood, C. S., Moir, R. D.et al. (1997). Zinc-induced Alzheimer's Aß1-40 aggregation is mediated by conformational factors.J. Biol. Chem., 272, 26464–70CrossRefGoogle Scholar
Huang, X., Atwood, C. S., Hartshorn, M. A.et al. (1999a). The Aß peptide of Alzheimer's Disease directly produces hydrogen peroxide through metal ion reduction.Biochemistry, 38, 7609–16CrossRefGoogle Scholar
Huang, X., Cuajungco, M. P., Atwood, C. S.et al. (1999b). Cu(II) potentiation of Alzheimer Aß neurotoxicity: correlation with cell-free hydrogen peroxide production and metal reduction.J. Biol. Chem., 274, 37111–16CrossRefGoogle Scholar
Jacob, C., Maret, W. & Vallee, B. L. (1998). Control of zinc transfer between thionein, metallothionein, and zinc proteins.Proc. Natl Acad. Sci., USA, 95(7), 3489–94CrossRefGoogle ScholarPubMed
Kang, J., Lemaire, H. G., Unterbeck, A.et al. (1987). The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.Nature, 325, 733–6CrossRefGoogle ScholarPubMed
Kapaki, E. N., Zournas, C. P., Segdistsa, I. T., Xenos, D. S. & Papageorgiou, C. T. (1993). Cerebrospinal fluid aluminum levels in Alzheimer's disease.Biol. Psychiatr., 33(8–9): 679–81CrossRefGoogle ScholarPubMed
Kapaki, E., Zournas, C., Kanias, G., Zambelis, T., Kakami, A. & Papageorgiou, C. (1997). Essential trace element alterations in amyotrophic lateral sclerosis.J. Neurol. Sci., 147(2), 171–5CrossRefGoogle ScholarPubMed
King, J. C., Shames, D. M. & Woodhouse, L. R. (2000). Zinc homeostasis in humans.J. Nutr., 130(5S Suppl), 1360S–6SCrossRefGoogle ScholarPubMed
Krebs, N. F. (2000). Overview of zinc absorption and excretion in the human gastrointestinal tract.J. Nutr., 130(5S Suppl), 1374S–7SCrossRefGoogle ScholarPubMed
Kuo, Y. M., Zhou, B., Cosco, D. & Gitschier, J. (2001). The copper transporter CTR1 provides an essential function in mammalian embryonic development.Proc. Natl Acad. Sci., USA, 98(12), 6836–41CrossRefGoogle ScholarPubMed
Leake, A., Morris, C. M. & Whateley, J. (2000). Brain matrix metalloproteinase 1 levels are elevated in Alzheimer's disease.Neurosci. Lett., 291(3), 201–3CrossRefGoogle ScholarPubMed
Lee, D. Y., Prasad, A. S., Hydrick-Adair, C., Brewer, G. & Johnson, P. E. (1993). Homeostasis of zinc in marginal human zinc deficiency: role of absorption and endogenous excretion of zinc.J. Lab. Clin. Med., 122(5), 549–56Google ScholarPubMed
Lee, J.-Y., Mook-Jung, I. & Koh, J.-Y. (1999). Histochemically reactive zinc in plaques of the Swedish mutant beta-amyloid precursor protein transgenic mice.J. Neurosci., 19, RC10, 1–5CrossRefGoogle ScholarPubMed
Lee, J., Prohaska, J. R. & Thiele, D. J. (2001). Essential role for mammalian copper transporter Ctr1 in copper homeostasis and embryonic development.Proc. Natl Acad. Sci., USA, 98(12), 6842–7CrossRefGoogle ScholarPubMed
Liochev, S. I., Chen, L. L., Hallewell, R. A. & Fridovich, I. (1997). Superoxide-dependent peroxidase activity of H48Q: a superoxide dismutase variant associated with familial amyotrophic lateral sclerosis.Arch. Biochem. Biophys., 346(2), 263–8CrossRefGoogle ScholarPubMed
Liu, H., Zhu, H., Eggers, D. K.et al. (2000). Copper(2+) binding to the surface residue cysteine 111 of His46Arg human copper-zinc superoxide dismutase, a familial amyotrophic lateral sclerosis mutant.Biochemistry, 39(28), 8125–32CrossRefGoogle ScholarPubMed
Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. & Markesbery, W. R. (1998). Copper, iron and zinc in Alzheimer's disease senile plaques.J. Neurol. Sci., 158(1), 47–52CrossRefGoogle ScholarPubMed
Maret, W. & Vallee, B. L. (1998). Thiolate ligands in metallothionein confer redox activity on zinc clusters.Proc. Natl Acad. Sci., USA, 95(7), 3478–82CrossRefGoogle ScholarPubMed
Masters, B. A., Quaife, C. J., Erickson, J. C.et al. (1994). Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles.J. Neurosci., 14, 5844–57CrossRefGoogle ScholarPubMed
Mattiazzi, M., D' Aurelio, M., Gajewski, C. D.et al. (2002). Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice.J. Biol. Chem., 277(33), 29626–33CrossRefGoogle ScholarPubMed
Maynard, C. J., Cappai, R., Volitakis, I.et al. (2002). Overexpression of Alzheimer's disease amyloid-beta opposes the age-dependent elevations of brain copper and iron.J. Biol. Chem., 277, 44670–6CrossRefGoogle ScholarPubMed
Mercer, J. F. (2001). The molecular basis of copper-transport diseases.Trends Mol. Med., 7(2), 64–9CrossRefGoogle ScholarPubMed
Miura, T., Suzuki, K., Kohata, N. & Takeuchi, H. (2000). Metal binding modes of Alzheimer's amyloid ß-peptide in insoluble aggregates and soluble complexes.Biochemistry, 39(23), 7024–31CrossRefGoogle Scholar
Moir, R. D., Atwood, C. S., Romano, D. M.et al. (1999). Differential effects of apolipoprotein E isoforms on metal-induced aggregation of Aß using physiological concentrations.Biochemistry, 38(14), 4595–603CrossRefGoogle Scholar
Molina, J. A., Jimenez-Jimenez, F. J., Aguilar, M. V.et al. (1998). Cerebrospinal fluid levels of transition metals in patients with Alzheimer's disease.J. Neural Transm., 105(4–5), 479–88CrossRefGoogle ScholarPubMed
Morita, H., Ikeda, S., Yamamoto, K.et al. (1995). Hereditary ceruloplasmin deficiency with hemosiderosis: a clinicopathological study of a Japanese family.Ann. Neurol., 37(5), 646–56CrossRefGoogle ScholarPubMed
Nagano, S., Ogawa, Y., Yanagihara, T. & Sakoda, S. (1999). Benefit of a combined treatment with trientine and ascorbate in familial amyotrophic lateral sclerosis model mice.Neurosci. Lett., 265(3), 159–62CrossRefGoogle ScholarPubMed
Nagano, S., Satoh, M., Sumi, H.et al. (2001). Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner.Eur. J. Neurosci., 13(7), 1363–70CrossRefGoogle ScholarPubMed
Nunomura, A., Perry, G., Aliev, G.et al. (2001). Oxidative damage is the earliest event in Alzheimer disease.J. Neuropathol. Exp. Neurol., 60(8), 759–67CrossRefGoogle ScholarPubMed
Opazo, C., Huang, X. & Cherny, R., (2002). Metalloenzyme-like activity of Alzheimer's disease ß-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological, reducing agents to neurotoxic H202. J. Biol. Chem., 277, 40302–8CrossRefGoogle Scholar
Palmiter, R. D. & Findley, S. D. (1995). Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc.EMBO J., 14(4), 639–49Google Scholar
Palmiter, R. D., Cole, T. B. & Findley, S. D. (1996a). ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration.EMBO J., 15(8), 1784–91Google Scholar
Palmiter, R. D., Cole, T. B., Quaife, C. J. & Findley, S. D. (1996b). ZnT-3, a putative transporter of zinc into synaptic vesicles.Proc. Natl Acad. Sci. USA, 93(25), 14934–9CrossRefGoogle Scholar
Panayi, A. E., Spyrou, N. M., Iversen, B. S., White, M. A. & Part, P. (2002). Determination of cadmium and zinc in Alzheimer's brain tissue using Inductively Coupled Plasma Mass Spectrometry.J. Neurol. Sci., 195(1), 1–10CrossRefGoogle ScholarPubMed
Penkowa, M., Giralt, M., Moos, T., Thomsen, P. S., Hernandez, J. & Hidalgo, J. (1999). Impaired inflammatory response to glial cell death in genetically metallothionein-I-and -II-deficient mice.Exp. Neurol., 156(1), 149–64CrossRefGoogle ScholarPubMed
Pullen, R. G., Franklin, P. A. & Hall, G. H. (1990). 65Zinc uptake from blood into brain and other tissues in the rat.Neurochem. Res., 15(10), 1003–8CrossRefGoogle ScholarPubMed
Puttaparthi, K., Gitomer, W. L., Krishnan, U., Son, M., Rajendran, B. & Elliott, J. L. (2002). Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins.J. Neurosci., 22(20), 8790–6CrossRefGoogle Scholar
Reaume, A. G., Elliott, J. L., Hoffman, E. K.et al. (1996). Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury.Nat. Genet., 13(1), 43–7CrossRefGoogle ScholarPubMed
Roe, J. A., Wiedau-Pazos, M., Moy, V. N., Goto, J. J., Gralla, E. B. & Valentine, J. S. (2002). In vivo peroxidative activity of FALS-mutant human CuZnSODs expressed in yeast.Free Radic. Biol. Med., 32(2), 169–74CrossRefGoogle Scholar
Rogers, J. T., Randall, J. D., Cahill, C. M.et al. (2002). An iron-responsive element type II in the 5′-untranslated region of the Alzheimer's amyloid precursor protein transcript.J. Biol. Chem., 277(47), 45518–28CrossRefGoogle ScholarPubMed
Rosen, D. R. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.Nature, 364(6435), 362CrossRefGoogle ScholarPubMed
Rulon, L. L., Robertson, J. D., Lovell, M. A., Deibel, M. A., Ehmann, W. D. & Markesber, W. R. (2000). Serum zinc levels and Alzheimer's disease.Biol. Trace Elem. Res., 75(1–3), 79–85CrossRefGoogle ScholarPubMed
Sahu, R. N., Pandey, R. S., Subhash, M. N., Arya, B. Y., Padmashree, T. S. & Srinivas, K. N. (1988). CSF zinc in Alzheimer's type dementia.Biol. Psychiatr., 24(4), 480–2CrossRefGoogle ScholarPubMed
Sandstead, H. H. (2000). Causes of iron and zinc deficiencies and their effects on brain.J. Nutr., 130(2S Suppl), 347S–9SCrossRefGoogle ScholarPubMed
Sillevis-Smitt, P. A., Blaauwgeers, H. G., Troost, D. & Jong, J. M. (1992). Metallothionein immunoreactivity is increased in the spinal cord of patients with amyotrophic lateral sclerosis.Neurosci. Lett., 144(1–2), 107–10CrossRefGoogle ScholarPubMed
Sillevis-Smitt, P. A., Mulder, T. P., Verspaget, H. W., Blaauwgeers, H. G., Troost, D. & Jong, J. M. (1994). Metallothionein in amyotrophic lateral sclerosis.Biol. Signal., 3(4), 193–7CrossRefGoogle ScholarPubMed
Singh, R. J., Karoui, H., Gunther, M. R., Beckman, J. S., Mason, R. P. & Kalyanaraman, B. (1998). Reexamination of the mechanism of hydroxyl radical adducts formed from the reaction between familial amyotrophic lateral sclerosis-associated Cu, Zn superoxide dismutase mutants and H2O2.Proc. Natl Acad. Sci., USA, 95(12), 6675–80CrossRefGoogle Scholar
Squitti, R., Rossini, P. M., Cassetta, E.et al. (2002). d-penicillamine reduces serum oxidative stress in Alzheimer's disease patients.Eur. J. Clin. Invest., 32(1), 51–9CrossRefGoogle ScholarPubMed
Strausak, D., Mercer, J. F., Dieter, H. H., Stremmel, W. & Multhaup, G. (2001). Copper in disorders with neurological symptoms: Alzheimer's, Menkes, and Wilson diseases.Brain Res. Bull., 55(2), 175–85CrossRefGoogle ScholarPubMed
Subramaniam, J. R., Lyons, W. E., Liu, J.et al. (2002). Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading.Nat. Neurosci., 5(4), 301–7CrossRefGoogle ScholarPubMed
Suh, S. W., Jensen, K. B., Jensen, M. S.et al. (2000). Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains.Brain Res., 852(2), 274–8CrossRefGoogle ScholarPubMed
Szerdahelyi, P. & Kasa, P. (1984). Histochemistry of zinc and copper.Int. Rev. Cytol., 89, 1–29CrossRefGoogle ScholarPubMed
Tanzi, R. E., Petrukhin, K., Chernov, I.et al. (1993). Identification of the Wilson's disease gene; a copper transporting ATPase with homology to the Menkes' disease gene.Nat. Genet., 3(4), 344–50CrossRefGoogle Scholar
Tully, C. L., Snowdon, D. A. & Markesbery, W. R. (1995). Serum zinc, senile plaques, and neurofibrillary tangles: findings from the Nun Study. NeuroReport, 6, 2105–8CrossRefGoogle ScholarPubMed
Uchida, Y., Ihara, Y. & Tomonaga, M. (1988). Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats.Biochem. Biophys. Res. Commun., 150(3), 1263–7CrossRefGoogle ScholarPubMed
Uchida, Y., Takio, K., Titani, K., Ihara, Y. & Tomonaga, M. (1991). The growth-inhibitory factor that is deficient in the Alzheimer's disease brain is a 68-amino acid metallothionein-like protein.Neuron, 7, 337–47CrossRefGoogle ScholarPubMed
Vallee, B. L. (1995). The function of metallothionein.Neurochem. Int., 27(1), 23–33CrossRefGoogle ScholarPubMed
Wang, K., Zhou, B., Kuo, Y. M., Zemansky, J. & Gitschier, J. (2002). A novel member of a zinc transporter family is defective in acrodermatitis enteropathica.Am. J. Hum. Genet., 71(1), 66–73CrossRefGoogle ScholarPubMed
Wenstrup, D., Ehmann, W. D. & Markesbery, W. R. (1990). Trace element imbalances in isolated subcellular fractions of Alzheimer's disease brains.Brain Res., 533(1), 125–31CrossRefGoogle ScholarPubMed
Wiedau-Pazos, M., Goto, J. J., Rabizadeh, S.et al. (1996). Altered reactivity of superoxide dismutase in familial amyotrophic lateral sclerosis.Science, 271(5248), 515–18CrossRefGoogle ScholarPubMed
Wong, P. C., Pardo, C. A., Borchelt, D. R.et al. (1995). An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.Neuron, 14(6), 1105–16CrossRefGoogle ScholarPubMed
Wong, P. C., Waggoner, D., Subramaniam, J. R.et al. (2000). Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase.Proc. Natl Acad. Sci., USA, 97(6), 2886–91CrossRefGoogle ScholarPubMed
Yasui, M., Ota, K. & Garruto, R. M. (1993). Concentrations of zinc and iron in the brains of Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia.Neurotoxicology, 14(4), 445–50Google ScholarPubMed
Yu, W. H., Lukiw, W. J., Bergeron, C., Niznik, H. B. & Fraser, P. E. (2001). Metallothionein III is reduced in Alzheimer's disease.Brain Res., 894(1), 37–45CrossRefGoogle ScholarPubMed
Zhou, H. & Thiele, D. J. (2001). Identification of a novel high affinity copper transport complex in the fission yeast Schizosaccharomyces pombe.J. Biol. Chem., 276(23), 20529–35CrossRefGoogle ScholarPubMed

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Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

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Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

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Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

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