ZINC-METABOLISM IN THE BRAIN - RELEVANCE TO HUMAN NEURODEGENERATIVE-DISORDERS

Zinc is an important trace element in biology. An important pool of zi nc in the brain is the one present in synaptic vesicles in a subgroup of glutamatergic neurons. In this form it can be released by electrica l stimulation and may serve to modulate responses at receptors for a n umber of different neurotransmitters. These include both excitatory an d inhibitory receptors, particularly the NMDA and GABA(A) receptors. T his pool of zinc is the only form of zinc readily stained histochemica lly (the chelatable zinc pool), but constitutes only about 8% of the t otal zinc content in the brain. The remainder of the zinc is more or l ess tightly bound to proteins where it acts either as a component of t he catalytic site of enzymes or in a structural capacity. The metaboli sm of zinc in the brain is regulated by a number of transport proteins , some of which have been recently characterized by gene cloning techn iques. The intracellular concentration may be mediated both by efflux from the cell by the zinc transporter ZrT1 and by complexing with apot hionein to form metallothionein. Metallothionein may serve as the sour ce of zinc for incorporation into proteins, including a number of DNA transcription factors. However, zinc is readily released from metallot hionein by disulfides, increasing concentrations of which are formed u nder oxidative stress. Metallothionein is a very good scavenger of fre e radicals, and zinc itself can also reduce oxidative stress by bindin g to thiol groups, decreasing their oxidation. Zinc is also a very pot ent inhibitor of nitric oxide synthase. Increased levels of chelatable zinc have been shown to be present in cell cultures of immune cells u ndergoing apoptosis. This is very reminiscent of the zinc staining of neuronal perikarya dying after an episode of ischemia or seizure activ ity. Thus a possible role of zinc in causing neuronal death in the bra in needs to be fully investigated. Intraventricular injections of calc ium EDTA have already been shown to reduce neuronal death after a peri od of ischemia. Pharmacological doses of zinc cause neuronal death, an d some estimates indicate that extracellular concentrations of zinc co uld reach neurotoxic levels under pathological conditions. Zinc is rel eased in high concentrations from the hippocampus during seizures. Unf ortunately, there are contrasting observations as to whether this zinc serves to potentiate or decrease seizure activity. Zinc may have an a dditional role in causing death in at least some neurons damaged by se izure activity and be involved in the sprouting phenomenon which may g ive rise to recurrent seizure propagation in the hippocampus. In Alzhe imer's disease, zinc has been shown to aggregate beta-amyloid, a form which is potentially neurotoxic. The zinc-dependent transcription fact ors NF-kappa B and Sp1 bind to the promoter region of the amyloid prec ursor protein (APP) gene. Zinc also inhibits enzymes which degrade APP to nonamyloidogenic peptides and which degrade the soluble form of be ta-amyloid. The changes in zinc metabolism which occur during oxidativ e stress may be important in neurological diseases where oxidative str ess is implicated, such as Alzheimer's disease, Parkinson's disease, a nd amyotrophic lateral sclerosis (ALS). Zinc is a structural component of superoxide dismutase 1, mutations in which give rise to one form o f familiar ALS. After HIV infection, zinc deficiency is found which ma y be secondary to immune-induced cytokine synthesis. Zinc is involved in the replication of the HIV virus at a number of sites. These observ ations should stimulate further research into the role of zinc in neur opathology. (C) 1997 Academic Press.