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  • Review Article
  • Published:

The neurobiology of zinc in health and disease

Nature Reviews Neuroscience volume 6, pages 449–462 (2005)Cite this article

Key Points

  • Long appreciated for its biological activity by the ancients, the zinc ion is now recognized as an important component of biological signalling cascades, with roles in practically every cell and tissue type. The role of zinc in central neuronal function and signalling is increasingly being appreciated. Of particular importance in both function and disease is the synaptic release of zinc from certain neurons by calcium-and impulse-dependent exocytosis. The neurons that release zinc in the mammalian cerebrum are all glutamatergic, and elaboration of the role that these neurons play in cerebral function is currently underway. The modulation of cortical excitability or 'tone' and the modulation of synaptic plasticity are two prominent theories.

  • 'Free' (rapidly exchangeable) Zn2+ is highly toxic. The 'safe' concentration of free zinc in the extracellular fluids of the brain is about 10 nM. Several proteins have been identified that modulate the uptake and export of zinc in all tissues, but only ZnT3 expression is unique to the brain, where it is confined to the synaptic vesicle membranes of a subset of glutamatergic fibres.

  • Zinc has two clear roles in brain injury and brain disease. First, neurons increase their intracellular 'free' zinc by ∼1,000–10,000-fold after excitotoxic injury (such as stroke). Buffering that free zinc back down to normal levels can rescue affected neurons from apoptotic death. Second, Zn2+, in tandem with oxidative damage, induces the precipitation of amyloid-β into amyloid plaques and congophilic angiopathy, the pathological hallmarks of Alzheimer's disease. Genetic ablation of ZnT3 abolishes amyloid deposition in a transgenic model of Alzheimer's disease.

  • Pharmacological therapies for excitotoxic brain injury and neurodegenerative brain disease based on the concept of buffering the free zinc in the brain (pZn) to the appropriate, physiological concentration (pZn ∼8) have been shown to be effective in preclinical models and are currently undergoing clinical trials. Some encouraging results have been obtained in both areas, with neuroprotection for stroke and slowed progression of symptoms in Alzheimer's disease.

  • Zinc signalling is also attracting attention outside the brain, where many cell types also secrete zinc. Now that the appropriate tools and techniques for imaging, quantifying and administering zinc are becoming available, research in this field is set to accelerate.

Abstract

The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus1), and zinc has apparently been used fairly steadily throughout Roman2 and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'.

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Figure 1: Intravital staining of mossy fibres in the rat using the fluorescent probe ZP1.
Figure 2: Synaptic zinc transport.
Figure 3: Zinc release into the extracellular fluid of a hippocampal slice induced by nitric oxide.
Figure 4: Zinc in the amyloid-β plaques of Alzheimer's disease.
Figure 5: Proposed model for pathogenic copper and zinc interaction with amyloid-β in Alzheimer's disease.
Figure 6: Extracellular zinc buffering.
Figure 7: Effect of zinc and copper chelation on amyloid neuropathology in a transgenic mouse model of Alzheimer's disease.

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Acknowledgements

A.I.B. is supported by funds from the National Institute on Aging, the National Health and Medical Research Council of Australia, the Australian Research Council Federation Fellowship, the Alzheimer's Association and the American Health Assistance Foundation

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Authors and Affiliations

  1. NeuroBio Tex, Inc., 101 Christopher Columbus Blvd, Galveston, 77550, Texas, USA

    Christopher J. Frederickson

  2. The University of Texas Medical School, Galveston, 77550, Texas, USA

    Christopher J. Frederickson

  3. Department of Neurology, National Creative Research Initiative Center for the Study of CNS Zinc, College of Medicine, University of Ulsan, Seoul, 138-736, South Korea

    Jae-Young Koh

  4. Oxidation Disorders Laboratory, Mental Health Research Institute of Victoria, and Department of Pathology, The University of Melbourne, 155 Oak Street, Larkville, 3052, Victoria, Australia

    Ashley I. Bush

  5. Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Harvard Medical School, Massachusetts General Hospital, Boston, 02129, Massachusetts, USA

    Ashley I. Bush

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  1. Christopher J. Frederickson
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Correspondence to Christopher J. Frederickson, Jae-Young Koh or Ashley I. Bush.

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A. I. B. is a shareholder and paid consultant for Prana Biotechnology Ltd.

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AIF

APLP1

APLP2

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MT3

NGFβ

nNOS

PARP

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S100β

ZnT3

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Frederickson, C., Koh, JY. & Bush, A. The neurobiology of zinc in health and disease. Nat Rev Neurosci 6, 449–462 (2005). https://doi.org/10.1038/nrn1671

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