Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β-Induced Excess Zn to Functional Zn Deficiency.

The role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn dysregulation remains unclear. Here, we report that hippocampal MT induction defends cognitive decline, which was induced by amyloid β (Aβ)-mediated excess Zn and functional Zn deficiency. Excess increase in intracellular Zn, which was induced by local injection of Aβ 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 Aβ-mediated Zn uptake, but not Aβ uptake, into dentate granule cells, also rescued Aβ-induced impairment of memory via attenuated LTP. The present study indicates that hippocampal MT induction blocks rapid excess increase in intracellular Zn in dentate granule cells, which originates in Zn released from Aβ, followed by rescuing Aβ-induced cognitive decline. Furthermore, LTP was vulnerable to Aβ in the aged dentate gyrus, consistent with enhanced Aβ-mediated Zn uptake into aged dentate granule cells, suggesting that Aβ-induced cognitive decline, which is caused by excess intracellular Zn, can more frequently occur along with aging. On the other hand, attenuated LTP under functional Zn 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 Zn concentration, while its induction is an attractive defense strategy against Aβ-induced cognitive decline.