Molecular Neurobiology · Feb 19, 2018
Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β₁₋₄₂-Induced Excess Zn²⁺ to Functional Zn²⁺ Deficiency
By Takeda A, Tamano H, Hashimoto W et al.
The role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn²⁺ dysregulation remains unclear. Here, we report that hippocampal MT induction defends cognitive decline, which was induced by amyloid β₁₋₄₂ (Aβ₁₋₄₂)-mediated excess Zn²⁺ and functional Zn²⁺ deficiency. Excess increase in intracellular Zn²⁺, which was induced by local injection of Aβ₁₋₄₂ into the dentate granule cell layer, attenuated in vivo perforant pathway LTP, while the attenuation was rescued by preinjection of MT inducers into the same region. Intraperitoneal injection of dexamethasone, which increased hippocampal MT proteins and blocked Aβ₁₋₄₂-mediated Zn²⁺ uptake, but not Aβ₁₋₄₂ uptake, into dentate granule cells, also rescued Aβ₁₋₄₂-induced impairment of memory via attenuated LTP. The present study indicates that hippocampal MT induction blocks rapid excess increase in intracellular Zn²⁺ in dentate granule cells, which originates in Zn²⁺ released from Aβ₁₋₄₂, followed by rescuing Aβ₁₋₄₂-induced cognitive decline. Furthermore, LTP was vulnerable to Aβ₁₋₄₂ in the aged dentate gyrus, consistent with enhanced Aβ₁₋₄₂-mediated Zn²⁺ uptake into aged dentate granule cells, suggesting that Aβ₁₋₄₂-induced cognitive decline, which is caused by excess intracellular Zn²⁺, can more frequently occur along with aging. On the other hand, attenuated LTP under functional Zn²⁺ deficiency in dentate granule cells was also rescued by MT induction. Hippocampal MT induction may rescue cognitive decline under lack of cellular transient changes in functional Zn²⁺ concentration, while its induction is an attractive defense strategy against Aβ₁₋₄₂-induced cognitive decline.