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ATP7B Variants as Modulators of Copper Dyshomeostasis in Alzheimer’s Disease

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Abstract

To understand the role of the key copper-regulating gene, ATP7B, in copper dyshomeostasis associated with Alzheimer’s disease (AD), we analyzed the serum levels of copper, ceruloplasmin and ‘free’ (i.e., non-ceruloplasmin bound) copper in 399 patients with AD and 303 elderly healthy controls. We also performed analyses of informative variants of ATP7B. AD patients had higher levels of copper and free copper than controls. Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p < 0.001). Among these individuals, those who were carriers of the ATP7B variants accounted for a large proportion of the free copper levels, specifically in the AD group (p < 0.01). Our results suggest the existence of a ‘copper dysfunction’ phenotype of sporadic AD which has a genetic basis. They also suggest that free copper is a risk factor for this disorder, modulating additional pathways leading to the disease cascade.

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Acknowledgments

This study was partially supported by the following grants: 1) European Community’s Seventh Framework Programme Project MEGMRI (no. 200859); 2) FISM—Fondazione Italiana Sclerosi Multipla—Cod.2010/R/38” Fatigue Relief in Multiple Sclerosis by Neuromodulation: a transcranial Direct Current Stimulation (tDCS) Intervention. [FaMuSNe]; 3) Italian Ministry of Health Cod. GR-2008-1138642 ‘Promoting recovery from Stroke: Individually enriched therapeutic intervention in Acute phase’ [ProSIA].

Conflict of interest

All authors and their family members report no financial relationship related to the manuscript or the topic and no conflicts of interest.

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Authors and Affiliations

  1. Department of Neuroscience, AFaR-Ospedale Fatebenefratelli Hospital, 00186, Rome, Italy

    Rosanna Squitti, Serena Bucossi, Mariacarla Ventriglia & Stefania Mariani

  2. Department of Neurology, “Campus Bio-Medico” University, Rome, Italy

    Rosanna Squitti, Mariacristina Siotto, Serena Bucossi, Mariacarla Ventriglia, Stefania Mariani, Fabrizio Vernieri, Federica Scrascia & Laura Trotta

  3. Department of Biology, “Tor Vergata” University, Rome, Italy

    Renato Polimanti

  4. Don Carlo Gnocchi Foundation ONLUS, Milan, Italy

    Mariacristina Siotto

  5. Department of Imaging, Casa di Cura San Raffaele, Cassino, Italy

    Paolo Maria Rossini

  6. Institute of Neurology, Catholic University, Rome, Italy

    Paolo Maria Rossini

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  1. Rosanna Squitti
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Correspondence to Rosanna Squitti.

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Rosanna Squitti and Renato Polimanti contributed equally to this work.

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Squitti, R., Polimanti, R., Siotto, M. et al. ATP7B Variants as Modulators of Copper Dyshomeostasis in Alzheimer’s Disease. Neuromol Med 15, 515–522 (2013). https://doi.org/10.1007/s12017-013-8237-y

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