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Characterization of the role of the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is by far the most commonly diagnosed dementia, and despite multiple efforts, there are still no effective drugs available for its treatment. One strategy that deserves to be pursued is to alter the expression and/or physiological action of endogenous proteins instead of administering exogenous factors. In this study, we intend to characterize the roles of the antioxidant, anti-inflammatory, and heavy-metal binding proteins, metallothionein-1 + 2 (MT1 + 2), in a mouse model of Alzheimer’s disease, Tg2576 mice. Contrary to expectations, MT1 + 2-deficiency rescued partially the human amyloid precursor protein-induced changes in mortality and body weight in a gender-dependent manner. On the other hand, amyloid plaque burden was decreased in the cortex and hippocampus in both sexes, while the amyloid cascade, neuroinflammation, and behavior were affected in the absence of MT1 + 2 in a complex manner. These results highlight that the control of the endogenous production and/or action of MT1 + 2 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. Hidalgo). Y. Manso acknowledges her Ph.D. fellowship (AP2005-0588). P.A. Adlard 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.

Conflict of interest

A.I. Bush 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. Adlard is a paid consultant and shareholder of Prana Biotechnology Ltd.

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Authors and Affiliations

  1. Animal Physiology Unit, Department of Cellular Biology, Physiology and Immunology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Edificio C, Bellaterra, Barcelona, 08193, Spain

    Yasmina Manso, Javier Carrasco, Gemma Comes & Juan Hidalgo

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

    Yasmina Manso, Gemma Comes & Juan Hidalgo

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

    Paul A. Adlard & Ashley I. Bush

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

    Paul A. Adlard

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  1. Yasmina Manso
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  4. Paul A. Adlard
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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 the antioxidant proteins metallothioneins 1 and 2 in an animal model of Alzheimer’s disease. Cell. Mol. Life Sci. 69, 3665–3681 (2012). https://doi.org/10.1007/s00018-012-1045-y

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