Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β1–42-Induced Excess Zn2+ to Functional Zn2+ Deficiency

Abstract

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.

In vivo synaptic activity-independent co-uptakes of amyloid β1–42 and Zn2+ into dentate granule cells in the normal brain

“…In the hippocampus, Aβ 1–42 released into the extracellular compartment can capture Zn 2+ , which is estimated to be approximately 10 nM in the extracellular fluid 13 , even at 500 pM Aβ 1–42 in vivo . We have reported that Aβ 1–42 takes Zn 2+ as a cargo into dentate granule cells in the normal brain, followed by cognitive decline 14–16 . Although the mechanism of Zn-Aβ 1–42 uptake remains to be solved, extracellular Zn 2+ is essential for Aβ 1–42 uptake into dentate granule cells 15 .…”

Age-Dependent Modification of Intracellular Zn²⁺ Buffering in the Hippocampus and Its Impact

“…44,45) The vulnerability seems to be linked with age-related modification of extracellular Zn 2+ influx, which is induced by glutamate and Aβ 1-42 in the extracellular compartment. 33,41,46,47)…”

“…59) The aggregating property of Aβ 1-42 is rapidly promoted with Zn 2+ , resulting in much higher affinity of Aβ 1-42 to Zn 2+ than that of Aβ 1-40 , and the K d values of Zn 2+ to Aβ 1-42 are in the range of 3-30 nM. 46) Aβ 1-42 , unlike Aβ 1-40 , captures extracellular Zn 2+ at high picomolar levels, and the formation of Zn-Aβ 1-42 in the extracellular compartment is essential for Aβ 1-42 uptake into dentate granule cells, followed by cognitive decline (Fig. 2).…”

“…When Zn-Aβ 1-42 formed is taken up into dentate granule cells, Zn 2+ can be released from Aβ 1-42 , resulting in an increase in neurotoxic Zn 2+ (Fig. 2), which is assessed based on the increase in intracellular ZnAF-2 fluorescence 46,62) (Fig. 1).…”

“…In vivo local co-injection of Aβ 1-42 and Ca ethylenediaminetetraacetic acid (EDTA), an extracellular Zn 2+ chelator, or CdCl 2 , a zinc-replacing metal, into the rat dentate gyrus prevents Aβ 1-42 -mediated impairments of LTP induced at perforant path-dentate granule cell synapses and of recognition memory. 46) However, CaEDTA and CdCl 2 are not adaptable for clinical use because they cannot permeate the blood-brain barrier.…”