The causes of progressive neurodegeneration, i.e., Alzheimer's disease (AD) and Parkinson's disease (PD) are unknown. The basal (static) concentration of intracellular Zn²⁺ is estimated to be approximately 100 pM and is extremely lower than that of intracellular Ca²⁺ (～100 nM), suggesting that intracellular Zn²⁺ homeostasis is crucial for neural function. Moreover, the basal concentration of extracellular Zn²⁺ is estimated to be approximately 10 nM and is age-relatedly increased based on age-related increase in brain extracellular Zn. We postulated that progressive neurodegeneration is due to age-related intracellular Zn²⁺ dysregulation, which is induced by rapid influx of extracellular Zn²⁺. Neuronal amyloid β_1-42 (Aβ_1-42) accumulation is considered an upstream event in the AD pathogenesis. Here we report that Zn-Aβ_1-42 oligomers formed in the extracellular compartment are synaptic activity-independently taken up into neurons, followed by rapid intracellular Zn²⁺ dysregulation. PD is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Here, we report a unique mechanism of nigral dopaminergic degeneration, in which rapid intracellular Zn²⁺ dysregulation via the production of reactive oxygen species, especially hydrogen peroxide causes PD in rats, which is induced by paraquart and 6-hydroxydopamine. I will talk about novel defense strategy against progressive neurodegeneration by controlling intracellular Zn²⁺ dysregulation.