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Coexistence of Copper in the Iron-Rich Particles of Aceruloplasminemia Brain

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Abstract

The interaction between iron and copper has been discussed in association with human health and diseases for many years. Ceruloplasmin, a multi-copper oxidase, is mainly involved in iron metabolism and its genetic defect, aceruloplasminemia (ACP), shows neurological disorders and diabetes associated with excessive iron accumulation, but little is known about the state of copper in the brain. Here, we investigated localization of these metals in the brains of three patients with ACP using electron microscopes equipped with an energy-dispersive x-ray analyzer. Histochemically, iron deposition was observed mainly in the basal ganglia and dentate nucleus, and to lesser degree in the cerebral cortex of the patients, whereas copper grains were not detected. X-ray microanalysis identified two types of iron-rich particles in their brains: dense bodies, namely hemosiderins, and their aggregated inclusions. A small number of hemosiderins and most inclusions contained a significant amount of copper which was enough for distinct Cu x-ray images. These copper-containing particles were observed more frequently in the putamen and dentate nucleus than the cerebral cortex. Coexistence of iron and copper was supported by good correlations in the molecular ratios between these two metals in iron-rich particles with Cu x-ray image. Iron-dependent copper accumulation in iron-rich particles may suggest that copper recycling is enhanced to meet the increased requirement of cuproproteins in iron overload brain. In conclusion, the iron-rich particles with Cu x-ray image were found in the ACP brain.

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Acknowledgments

The authors are grateful to Dr. Michiya Ohta (Department of Neurology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan) for kindly providing us with the brain tissues for case 1.

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Authors and Affiliations

  1. Department of Brain Disease Research, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan

    Kunihiro Yoshida

  2. Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan

    Kunihiro Yoshida & Shu-ichi Ikeda

  3. Department of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya, Japan

    Hisao Hayashi, Yasuaki Tatsumi & Koichi Kato

  4. Department of Medical Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Shinya Wakusawa, Ryota Shigemasa, Ryoji Koide & Tetsuya Ishikawa

  5. Department of Neurology, Matsumoto Medical Center, Matsumoto, Japan

    Shinji Ohara

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  1. Kunihiro Yoshida
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  2. Hisao Hayashi
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  3. Shinya Wakusawa
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  10. Shu-ichi Ikeda
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Correspondence to Kunihiro Yoshida.

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Electronic supplementary material

Supplementary Fig. 1

Element images for a hemosiderin particle in the putamen of the DM1 patient. This figure was obtained with the 100 sweep cycles. This hemosiderin was small and lysosomal in size, and heterogeneous for inner structures with a high electron density (upper left). An Fe image first appeared with 25 sweep cycles, and then, both Fe and Cu images appeared with 100 sweep cycles, expressed as Fe/Cu hemosiderin (upper middle, upper right). Note that O (lower left), S (lower middle), and P (lower right) also accumulate in the hemosiderin. Bars = 0.5 μm. It may be important that most hemosiderins in the controls contain similar amount of copper to the surrounding cytoplasm, so that the iron image of hemosiderin, but not copper image appears with 100 sweep cycles (figures not shown). (GIF 463 kb)

High resolution image (TIFF 917 kb)

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Yoshida, K., Hayashi, H., Wakusawa, S. et al. Coexistence of Copper in the Iron-Rich Particles of Aceruloplasminemia Brain. Biol Trace Elem Res 175, 79–86 (2017). https://doi.org/10.1007/s12011-016-0744-x

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  • DOI: https://doi.org/10.1007/s12011-016-0744-x

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