The neurobiology of zinc in health and disease

Abstract

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.