Session V, Zinc and the Central Nervous System
Zinc and Health: Workshop Summary
Session V, Zinc and the Central Nervous System focused on the
anatomy, physiology, functional implications, and the pathology of
zinc in the CNS. The fact that zinc is present in two distinctly different
"pools" in the brain was recognized as an important starting point for
discussion. The major pool, which is protein-bound, was recognized as an
essential component of literally dozens of zinc metalloenzymes and
other zinc metalloproteins. These zinc metalloproteins are ubiquitous in
all soft tissue and in essentially all organelles of all cells.
The other pool (synaptic zinc) was described as small in quantity
(less that 5% of the total zinc) but large in functional significance.
The synaptic zinc was described as the small pool that is stored
exclusively in the presynaptic vesicles of certain forebrain neurons, and
released in a calcium- and impulse dependent fashion, resulting in transitory
"surges" of free or weakly-bound Zn2+ ion appearing in the brain's extracellular
fluid. These zinc-containing neurons were shown to be almost exclusively
located in cerebrocortical (especially allocortical) and amygdalar circuit,
releasing their Zn2+ signals primarily in those brain regions. The impact
of Zn2+ signals upon post-synaptic receptors (especially amino acid receptors)
and the neurotoxic effects of excess synaptically- released Zn2+
(as occurs in seizures, ischemia, and head trauma) were both reviewed.
The turnover and life-cycle of presynaptic vesicular zinc was
also a focus of interest. After synaptic release into the cleft,
zinc ions are taken up into the boutons by a high-affinity, energy-dependent
transport process associated with the boutons. This uptake can replenish
the vesicles, possibly working in concert with the ZnT-3 protein found
exclusively in the presynaptic vesicles of zinc-containing synaptic boutons.
The role of zinc in cognitive function has been studied extensively
in both children and the elderly. It was noted that zinc deficiency
during fetal life is associated with developmental delays; that zinc repletion
in children with zinc deficient gestations may not be adequate to improve
all of the developmental consequences. Low serum zinc levels in elders
are associated with poorer global cognitive function, particularly verbal
function, and that there is an inverse correlation of zinc blood levels
with plaque density in Alzheimer's disease. Lower serum zinc levels are
associated with slower lower extremity function and poorer activities of
daily living. Repletion in elders with lower serum zinc levels is associated
with improved, but variable cognitive function, and especially with activities
of daily living. It was noted that zinc's most important cognitive
effects may be mediated in conjunction with other micronutrients.
Zinc deficiency is likely an exacerbating or accelerating factor associated
with the syndrome of anorexia nervosa. Studying the changes in appetite
regulation, such as the "leptin-NPY-appetite axis" during zinc deficiency
may prove to be a useful model for physiologic changes occurring during
anorexia nervosa. The impact of zinc deficiency upon food intake
may also be mediated in part by the paleophobia triggered by malnutrition.
Evidence was presented showing an intimate association of zinc and Alzheimer's
disease in the terms of the pathogenesis of Alzheimer's. Zinc may
play a role in the elaboration of the apoptotic pathways that are governed
by zinc concentrations within the brain, and may also impact on the generation
of neurofibrillary tangle formation and the basic biology of tubulin assembly.
Alzheimer's disease is characterized by amyloid deposits within the neocortical
parenchyma and within the cerebrovascular area of the brain. Evidence was
presented showing that these amyloid deposits are selectively enriched
in zinc and showing that zinc chelation may dissolve amyloid lesions.
The possible use of zinc chelators as a therapeutic approach to treat neuro-toxicities
derived from any amyloid deposits has been considered.