[Brain Function and Pathophysiology Focused on Zn²⁺ Dynamics].

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Basal intracellular and extracellular Zn²⁺ levels in the brain are approximately 100 pM and 10 nM, respectively.
• Extracellular Zn²⁺ dynamics influence cognitive functions and neurodegenerative processes, interacting with glutamate and amyloid-β_1-42 (Aβ_1-42).

Purpose of the Study:

• To review the multifaceted roles of Zn²⁺ in the brain, including its neurotoxic effects.
• To explore metallothioneins as a potential therapeutic strategy against Aβ_1-42-induced pathogenesis.

Main Methods:

• Literature review synthesizing current research on Zn²⁺ homeostasis, signaling, and its role in neurodegeneration.
• Analysis of the interaction between Zn²⁺, Aβ_1-42, aging, and the protective mechanisms of metallothioneins.

Main Results:

• Intracellular Zn²⁺ signaling is crucial for learning and memory, while its dysregulation contributes to cognitive decline.
• Amyloid-β_1-42 captures extracellular Zn²⁺, leading to intracellular Zn²⁺ dysregulation, particularly with aging, exacerbating cognitive decline and neurodegeneration.
• Metallothioneins act as intracellular Zn²⁺ buffers, mitigating Zn²⁺ toxicity from Zn-Aβ_1-42 complexes.

Conclusions:

• Zn²⁺ plays a dual role in brain function, essential for cognition but toxic when dysregulated.
• Aging exacerbates Aβ_1-42-induced neurotoxicity through altered Zn²⁺ homeostasis.
• Metallothioneins offer a promising endogenous defense mechanism against Aβ_1-42-related neurodegeneration.