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Metallothionein biology in the ageing and neurodegenerative brain

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Abstract

In recent years metallothionein (MT) biology has moved from investigation of its ability to protect against environmental heavy metals to a wider appreciation of its role in responding to cellular stress, whether as a consequence of normal function, or following injury and disease. This is exemplified by recent investigation of MT in the mammalian brain where plausible roles for MT action have been described, including zinc metabolism, free radical scavenging, and protection and regeneration following neurological injury. Along with other laboratories we have used several models of central nervous system (CNS) injury to investigate possible parallels between injury-dependent changes in MT expression and those observed in the ageing and/or degenerating brain. Therefore, this brief review aims to summarise existing information on MT expression during CNS ageing, and to examine the possible involvement of this protein in the course of human neurodegenerative disease, as exemplified by Alzheimer’s disease.

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References

  • Acarin L, J Carrasco, B Gonzalez, J Hidalgo and B Castellano (1999) Expression of growth inhibitory factor (metallothioneinIII) mRNA and protein following excitotoxic immature brain injury.J. Neuropathol. Exp. Neurol. 58, 389–397.

    Article  PubMed  CAS  Google Scholar 

  • Adlard PA, AK West and JC Vickers (1998) Increased density of metallothionein I/II-immunopositive cortical glial cells in the early stages of Alzheimer’s disease.Neurobiol. Dis. 5, 349–356.

    Article  PubMed  CAS  Google Scholar 

  • Amoureux MC, D Van Gool, MT Herrero, R Dom, FC Colpaert and PJ Pauwels (1997) Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired.Mol. Chem. Neuropathol. 32, 101–121.

    Article  PubMed  CAS  Google Scholar 

  • Anezaki T, H Ishiguro, I Hozumi, T Inuzuka, M Hiraiwa, H Kobayashi, T Yuguchi, A Wanaka, Y Uda, T Miyatakeet al. (1995) Expression of growth inhibitory factor (GIF) in normal and injured rat brains.Neurochem. Int. 27, 89–94.

    Article  PubMed  CAS  Google Scholar 

  • Aschner M (1998) Metallothionein (MT) isoforms in the central nervous system (CNS): regional and cell-specific distribution and potential functions as an antioxidant.Neurotoxicology 19, 653–660.

    PubMed  CAS  Google Scholar 

  • Blaauwgeers HG, PA Sillevis Smitt, JM De Jong and D Troost (1993) Distribution of metallothionein in the human central nervous system.Glia 8, 62–70.

    Article  PubMed  CAS  Google Scholar 

  • Carrasco J, M Giralt, A Molinero, M Penkowa, T Moos and J Hidalgo (1999) Metallothionein (MT)-III: generation of polyclonal antibodies, comparison with MT-I+II in the freeze lesioned rat brain and in a bioassay with astrocytes, and analysis of Alzheimer’s disease brains.J. Neurotrauma 16, 1115–1129.

    Article  PubMed  CAS  Google Scholar 

  • Carrasco J, M Penkowa, M Giralt, J Camats, A Molinero, IL Campbell, RD Palmiter and J Hidalgo (2003) Role of metallothionein-III following central nervous system damage.Neurobiol. Dis. 13, 22–36.

    Article  PubMed  CAS  Google Scholar 

  • Chen L, W Wu, T Dentchev, R Wong and JL Dunaief (2004) Increased metallothionein in light damaged mouse retinas.Exp. Eye Res. 79, 287–293.

    Article  PubMed  CAS  Google Scholar 

  • Chung RS and AK West (2004) A role for extracellular metallothioneins in CNS injury and repair.Neuroscience 123, 595–599.

    Article  PubMed  CAS  Google Scholar 

  • Chung RS, JC Vickers, MI Chuah, BL Eckhardt and AK West (2002a) Metallothionein-III inhibits initial neurite formation in developing neurons as well as postinjury, regenerative neurite sprouting.Exp. Neurol. 178, 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Chung RS, AF Holloway, BL Eckhardt, JA Harris, JC Vickers, MI Chuah and AK West (2002b) Sheep have an unusual variant of the brain-specific metallothionein, metallothionein-III.Biochem. J. 365, 323–328.

    Article  PubMed  CAS  Google Scholar 

  • Chung RS, JC Vickers, MI Chuah and AK West (2003) Metallothionein-IIA promotes initial neurite elongation and postinjury reactive neurite growth and facilitates healing after focal cortical brain injury. J. Neurosci.23, 3336–3342.

    PubMed  CAS  Google Scholar 

  • Coyle P, JC Philcox, LC Carey and AM Rofe (2002) Metallothionein: the multipurpose protein.Cell. Mol. Life Sci. 59, 627–647.

    Article  PubMed  CAS  Google Scholar 

  • Dickson TC, PA Adlard and JC Vickers (2000) Sequence of cellular changes following localized axotomy to cortical neurons in glia-free culture.J. Neurotrauma 17, 1095–1103.

    Article  PubMed  CAS  Google Scholar 

  • Duguid JR, CW Bohmont, NG Liu and WW Tourtellotte (1989) Changes in brain gene expression shared by scrapie and Alzheimer disease.Proc. Natl. Acad. Sci USA 86, 7260–7264.

    Article  PubMed  CAS  Google Scholar 

  • Eddleston M and L Mucke (1993) Molecular profile of reactive astrocytes—implications for their role in neurologic disease.Neuroscience 54, 15–36.

    Article  PubMed  CAS  Google Scholar 

  • Erickson JC, AK Sewell, LT Jensen, DR Winge and RD Palmiter (1994) Enhanced neurotrophic activity in Alzheimer’s disease cortex is not associated with down-regulation of metallothioneinIII (GIF).Brain Res. 649, 297–304.

    Article  PubMed  CAS  Google Scholar 

  • Giacconi R, C Cipriano, M Muzzioli, N Gasparini, F Orlando and E Mocchegiani (2003) Interrelationships among brain, endocrine and immune response in ageing and successful ageing: role of metallothionein III isoform.Mech. Ageing Dev. 124, 371–378.

    Article  PubMed  CAS  Google Scholar 

  • Hidalgo J, M Aschner, P Zatta and M Vasak (2001) Roles of the metallothionein family of proteins in the central nervous system.Brain Res. Bull. 55, 133–145.

    Article  PubMed  CAS  Google Scholar 

  • Hidalgo J, M Penkowa, M Giralt, J Carrasco and A Molinero (2002) Metallothionein expression and oxidative stress in the brain.Methods Enzymol. 348, 238–249.

    Article  PubMed  CAS  Google Scholar 

  • Irie Y and WM Keung (2001) Metallothionein-III antagonizes the neurotoxic and neurotrophic effects of amyloid beta peptides.Biochem. Biophys. Res. Commun. 282, 416–420.

    Article  PubMed  CAS  Google Scholar 

  • Irie Y and WM Keung (2003) Anti-amyloid beta activity of metallothionein-III is different from its neuronal growth inhibitory activity: structure-activity studies.Brain Res. 960, 228–234.

    Article  PubMed  CAS  Google Scholar 

  • Kojima S, A Shimada, T Morita, Y Yamano and T Umemura (1999) Localization of metallothioneins-I & -II and -III in the brain of aged dog.J. Vet. Med. Sci. 61, 343–349.

    Article  PubMed  CAS  Google Scholar 

  • Kramer KK, J Liu, S Choudhuri and CD Klaassen (1996) Induction of metallothionein mRNA and protein in murine astrocyte cultures.Toxicol. Appl. Pharmacol. 136, 94–100.

    Article  PubMed  CAS  Google Scholar 

  • Lee CK, R Weindruch and TA Prolla (2000) Gene-expression profile of the ageing brain in mice.Nat. Genet. 25, 294–297.

    Article  PubMed  CAS  Google Scholar 

  • Masters BA, CJ Quaife, JC Erickson, EJ Kelly, GJ Froelick, BP Zambrowicz, RL Brinster and RD Palmiter (1994) Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles.J. Neurosci. 14, 5844–5857.

    PubMed  CAS  Google Scholar 

  • McGeer PL and EG McGeer (2002) Local neuroinflammation and the progression of Alzheimer’s disease.J. Neurovirol. 8, 529–538.

    Article  PubMed  CAS  Google Scholar 

  • Miyazaki I, M Asanuma, Y Higashi, CA Sogawa, K Tanaka and N Ogawa (2002) Age-related changes in expression of metallothionein-III in rat brain.Neurosci. Res. 43, 323–333.

    Article  PubMed  CAS  Google Scholar 

  • Mocchegiani E, R Giacconi, C Cipriano, M Muzzioli, P Fattoretti, C Bertoni-Freddari, G Isani, P Zambenedetti and P Zatta (2001) Zinc-bound metallothioneins as potential biological markers of ageing.Brain Res. Bull. 55, 147–153.

    Article  PubMed  CAS  Google Scholar 

  • Molinero A, M Penkowa, J Hernandez, J Camats, M Giralt, N Lago, J Carrasco, IL Campbell and J Hidalgo (2003) Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6.J. Neuropathol. Exp. Neurol. 62, 315–328.

    PubMed  CAS  Google Scholar 

  • Nagano S, M Satoh, H Sumi, H Fujimura, C Tohyama, T Yanagihara and S Sakoda (2001) Reduction of metallothioneins promotes the disease expression of familial amyotrophic lateral sclerosis mice in a dose-dependent manner.Eur. J. Neurosci. 13, 1363–1370.

    Article  PubMed  CAS  Google Scholar 

  • Nakajima K and K Suzuki (1995) Immunochemical detection of metallothionein in brain.Neurochem. Int. 27, 73–87.

    Article  PubMed  CAS  Google Scholar 

  • Natale JE, JB Knight, Y Cheng, JE Rome and V Gallo (2004) Metallothionein I nd II mitigate age-dependent secondary brain injury.J. Neurosci. Res. 78, 303–314.

    Article  PubMed  CAS  Google Scholar 

  • Nichols NR (1999) Glial responses to steroids as markers of brain ageing.J. Neurobiol. 40, 585–601.

    Article  PubMed  CAS  Google Scholar 

  • Peinado MA, A Quesada, JA Pedrosa, MI Torres, M Martinez, FJ Esteban, ML Del Moral, R Hernandez, J Rodrigo and JM Peinado (1998) Quantitative and ultrastructural changes in glia and pericytes in the parietal cortex of the ageing rat.Microsc. Res. Tech. 43, 34–42.

    Article  PubMed  CAS  Google Scholar 

  • Penkowa M, C Espejo, EM Martinez-Caceres, X Montalban and J Hidalgo (2003) Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis.Cell. Mol. Life Sci. 60, 185–197.

    Article  PubMed  CAS  Google Scholar 

  • Pilegaard K and O Ladefoged (1996) Total number of astrocytes in the molecular layer of the dentate gyrus of rats at different ages.Anal. Quant. Cytol. Histol. 18, 279–285.

    PubMed  CAS  Google Scholar 

  • Puttaparthi K, WL Gitomer, U Krishnan, M Son, B Rajendran and JL Elliott (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, 8790–8796.

    PubMed  CAS  Google Scholar 

  • Ren H, Q Ji, Y Liu and B Ru (2001) Different protective roles in vitro of alpha- and beta-domains of growth inhibitory factor (GIF) on neuron injuries caused by oxygen free radicals.Biochim. Biophys. Acta 1568, 129–134.

    PubMed  CAS  Google Scholar 

  • Richarz AN and P Bratter (2002) Speciation analysis of trace elements in the brains of individuals with Alzheimer’s disease with special emphasis on metallothioneins.Anal. Bioanal. Chem. 372, 412–417 Epub 2002 Jan. 2002.

    Article  PubMed  CAS  Google Scholar 

  • Rozovsky I, CE Finch and TE Morgan (1998) Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of ageing, increased proliferation, and resistance to down-regulation.Neurobiol. Ageing 19, 97–103.

    Article  CAS  Google Scholar 

  • Sato M and M Kondoh (2002) Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals.Tohoku. J. Exp. Med. 196, 9–22.

    Article  PubMed  CAS  Google Scholar 

  • Sheng JG, RE Mrak, CR Rovnaghi, E Kozlowska, LJ Van Eldik and WS Griffin (1996) Human brain S100 beta and S100 beta mRNA expression increases with age: pathogenic implications for Alzheimer’s disease.Neurobiol. Ageing 17, 359–363.

    Article  CAS  Google Scholar 

  • Sogawa CA, M Asanuma, N Sogawa, I Miyazaki, T Nakanishi, H Furuta and N Ogawa (2001) Localization, regulation, and function of metallothionein-III/growth inhibitory factor in the brain.Acta Med. Okayama 55, 1–9.

    PubMed  CAS  Google Scholar 

  • Suzuki K, K Nakajima, N Otaki, M Kimura, U Kawaharada, K Uehara, F Hara, Y Nakazato and M Takatama (1994) Localization of metallothionein in aged human brain.Pathol. Int. 44, 20–26.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki T, H Yamanaka, Y Tamura, K Nakajima, K Kanatani, M Kimura and N Otaki (1992a) Metallothionein of prostatic tissues and fluids in rats and humans.Tohoku. J. Exp. Med. 166, 251–257.

    Article  PubMed  CAS  Google Scholar 

  • Suzuki T, H Yamanaka, K Nakajima, K Suzuki, K Kanatani, M Kimura, C Ohma and N Otaki (1992b) Immunohistochemical study of metallothionein in human seminal vesicles.Tohoku. J. Exp. Med. 167, 127–134.

    Article  PubMed  CAS  Google Scholar 

  • Tsuji S, H Kobayashi, Y Uchida, Y Ihara and T Miyatake (1992) Molecular cloning of human growth inhibitory factor cDNA and its down- regulation in Alzheimer’s disease.EMBO J. 11, 4843–4850.

    PubMed  CAS  Google Scholar 

  • Uchida Y and M Tomonaga (1989) Neurotrophic action of Alzheimer’s disease brain extract is due to the loss of inhibitory factors for survival and neurite formation of cerebral cortical neurons.Brain Res. 481, 190–193.

    Article  PubMed  CAS  Google Scholar 

  • Uchida Y, K Takio, K Titani, Y Ihara and M Tomonaga (1991) The growth inhibitory factor that is deficient in the Alzheimer’s disease brain is a 68 amino acid metallothionein-like protein.Neuron 7, 337–347.

    Article  PubMed  CAS  Google Scholar 

  • Vickers JC (1997) A cellular mechanism for the neuronal changes underlying Alzheimer’s disease.Neuroscience 78, 629–639.

    Article  PubMed  CAS  Google Scholar 

  • Young JK, JS Garvey and PC Huang (1991) Glial immunoreactivity for metallothionein in the rat brain. Glia4, 602–610.

    Article  PubMed  CAS  Google Scholar 

  • Yu WH, WJ Lukiw, C Bergeron, HB Niznik and PE Fraser (2001) Metallothionein III is reduced in Alzheimer’s disease.Brain Res. 894, 37–45.

    Article  PubMed  CAS  Google Scholar 

  • Zambenedetti P, R Giordano and P Zatta (1998) Metallothioneins are highly expressed in astrocytes and microcapillaries in Alzheimer’s disease.J. Chem. Neuroanat. 15, 21–26.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. NeuroRepair Group, School of Medicine, University of Tasmania, 7001, Tasmania, Australia

    J. Dittmann, S. J. Fung, J. C. Vickers, M. I. Chuah, R. S. Chung & A. K. West

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  1. J. Dittmann
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  2. S. J. Fung
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  3. J. C. Vickers
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  4. M. I. Chuah
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  5. R. S. Chung
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  6. A. K. West
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Correspondence to A. K. West.

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Dittmann, J., Fung, S.J., Vickers, J.C. et al. Metallothionein biology in the ageing and neurodegenerative brain. neurotox res 7, 87–93 (2005). https://doi.org/10.1007/BF03033779

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  • DOI: https://doi.org/10.1007/BF03033779

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