Age-Dependent Modification of Intracellular Zn²⁺ Buffering in the Hippocampus and Its Impact

Abstract

The basal concentrations of extracellular Zn 2 and intracellular Zn 2 , which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca 2 (1.3 mM) and intracellular Ca 2 (100 nM), respectively, resulting in much less attention paid to Zn 2 than to Ca 2. However, intracellular Zn 2 dysregulation, which is closely linked with glutamate-and amyloid β-mediated extracellular Zn 2 influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca 2 dysregulation. It is estimated that the age-dependent increase in the basal concentration of extracellular Zn 2 in the hippocampus plays a key role in cognitive decline and neurodegeneration. The characteristics of extracellular Zn 2 influx in the hippocampus may be modified age-dependently, probably followed by modification of intracellular Zn 2 buffering that is closely linked with age-related cognitive decline and neurodegeneration. Reduction of intracellular Zn 2-buffering capacity may be linked with the pathophysiology of progressive neurodegeneration such as Alzheimer's disease. This paper deals with age-dependent modification of intracellular Zn 2 buffering in the hippocampus and its impact. On the basis of the estimated impact, we propose a potential defense strategy against Zn 2-mediated neurodegeneration, i.e., metallothionein induction in the hippocampus.

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