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Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease

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Abstract

Among the dementias, Alzheimer’s disease (AD) is the most commonly diagnosed, but there are still no effective drugs available for its treatment. It has been suggested that metallothionein-3 (MT-3) could be somehow involved in the etiology of AD, and in fact very promising results have been found in in vitro studies, but the role of MT-3 in vivo needs further analysis. In this study, we analyzed the role of MT-3 in a mouse model of AD, Tg2576 mice, which overexpress human Amyloid Precursor Protein (hAPP) with the Swedish mutation. MT-3 deficiency partially rescued the APP-induced mortality of females, and mildly affected APP-induced changes in behavior assessed in the hole-board and plus-maze tests in a gender-dependent manner. Amyloid plaque burden and/or hAPP expression were decreased in the cortex and hippocampus of MT-3-deficient females. Interestingly, exogenously administered Zn7MT-3 increased soluble Aβ40 and Aβ42 and amyloid plaques and gliosis, particularly in the cortex, and changed several behavioral traits (increased deambulation and exploration and decreased anxiety). These results highlight that the control of the endogenous production and/or action of MT-3 could represent a powerful therapeutic target in AD.

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Acknowledgments

The authors are grateful for grants from the Ministerio de Ciencia e Innovación y Cofinanciada por el Fondo Europeo de Desarrollo Regional (FEDER), SAF2002-01268, SAF2005-00671, SAF2008-00435, and SAF2011-23272 (J.H.). Y.M. acknowledges her Ph.D. fellowship (AP2005-0588). P.A. is supported by the National Health and Medical Research Council of Australia, The Australian Research Council, The Alzheimer’s Association (USA), and the Joan and Peter Clemenger Trust. A.B. is a paid consultant and shareholder of Prana Biotechnology Ltd, and a paid consultant of Adenoa Inc, and a shareholder of Brighton Biotech Inc. P.A is a paid consultant and shareholder of Prana Biotechnology Ltd.

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  1. Gabriele Meloni

    Present address: Division of Chemistry and Chemical Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, 91125, USA

Authors and Affiliations

  1. Unidad de Fisiología Animal, Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Biociencias, Universidad Autónoma de Barcelona, Edificio C, Bellaterra, 08193, Barcelona, Spain

    Yasmina Manso, Javier Carrasco, Gemma Comes & Juan Hidalgo

  2. Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, 08193, Barcelona, Spain

    Yasmina Manso, Gemma Comes & Juan Hidalgo

  3. Department of Biochemistry, University of Zürich, 8057, Zurich, Switzerland

    Gabriele Meloni & Milan Vašák

  4. Oxidation Biology Laboratory, The Mental Health Research Institute, The University of Melbourne, Parkville, VIC, 3052, Australia

    Paul A. Adlard

  5. Synaptic Neurobiology Laboratory, The Mental Health Research Institute, The University of Melbourne, Parkville, VIC, 3052, Australia

    Paul A. Adlard & Ashley I. Bush

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  1. Yasmina Manso
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  2. Javier Carrasco
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  3. Gemma Comes
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  4. Gabriele Meloni
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  5. Paul A. Adlard
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  6. Ashley I. Bush
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  7. Milan Vašák
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  8. Juan Hidalgo
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Correspondence to Juan Hidalgo.

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Manso, Y., Carrasco, J., Comes, G. et al. Characterization of the role of metallothionein-3 in an animal model of Alzheimer’s disease. Cell. Mol. Life Sci. 69, 3683–3700 (2012). https://doi.org/10.1007/s00018-012-1047-9

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  • DOI: https://doi.org/10.1007/s00018-012-1047-9

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