The basal levels of intracellular Zn²⁺ and extracellular Zn²⁺ are in the range of ～100 pM and ～10 nM, respectively, in the brain. Extracellular Zn²⁺ dynamics is involved in both cognitive performance and neurodegeneration. The bidirectional actions are linked with extracellular glutamate and amyloid-β_1-42 (Aβ_1-42). Intracellular Zn²⁺ signaling via extracellular glutamate is required for learning and memory, while intracellular Zn²⁺ dysregulation induces cognitive decline. Furthermore, human Aβ_1-42, a causative peptide in Alzheimer's disease pathogenesis captures extracellular Zn²⁺ and readily taken up into hippocampal neurons followed by intracellular Zn²⁺ dysregulation. Aβ_1-42-mediated intracellular Zn²⁺ dysregulation is accelerated with aging, because extracellular Zn²⁺ is age-relatedly increased, resulting in Aβ_1-42-induced cognitive decline and neurodegeneration with aging. On the other hand, metallothioneins, zinc-binding proteins can capture Zn²⁺ released from intracellular Zn-Aβ_1-42 complexes and serve for intracellular Zn²⁺-buffering to maintain intracellular Zn²⁺ homeostasis. This review summarizes Zn²⁺ function and its neurotoxicity in the brain, and also the potential defense strategy via metallothioneins against Aβ_1-42-induced pathogenesis.