Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β_1–42 Neurotoxicity Linked with Modified Extracellular Zn²⁺ Dynamics?

Abstract

The basal levels of extracellular Zn²⁺ are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn²⁺ dynamics is critical for cognitive activity and excess influx of extracellular Zn²⁺ into hippocampal neurons is a known cause of cognitive decline. The dentate gyrus is vulnerable to aging in the hippocampus and affected in the early stage of Alzheimer’s disease (AD). The reasons remain unclear. Neurogenesis-related apoptosis may induce non-specific neuronal depolarization by efflux of intracellular K⁺ in the dentate gyrus and be markedly increased along with aging. Extracellular Zn²⁺ influx into dentate granule cells via high K⁺-induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn²⁺ dynamics in the dentate gyrus of aged rats is linked with vulnerability to cognitive decline. Amyloid-β_1–42 (Aβ_1–42) is a causative candidate for AD pathogenesis. When Aβ_1–42 concentration reaches picomolar in the extracellular compartment in the dentate gyrus, Zn–Aβ_1–42 is formed in the extracellular compartment and rapidly taken up into dentate granule cells, followed by Aβ_1–42-induced cognitive decline that is due to Zn²⁺ released from Aβ_1–42, suggesting that dentate granule cells are sensitive to extracellular Zn²⁺-dependent Aβ_1–42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ_1–42 neurotoxicity.

1. INTRODUCTION

Hippocampal formation is a key area for memory and recognition of novelty and is composed of the entorhinal cortex, the dentate gyrus, the CA3 and the CA1 subfields, and the subiculum. Information on memory from the entorhinal cortex is input to the dentate gyrus and processed by an unidirectional circuit, i.e., the dentate gyrus–CA3–CA1 trisynaptic circuits and the subiculum.^1,2) The entorhinal cortex is also directly connected with the CA3 and the CA1 subfields, in addition to the dentate gyrus.³⁾ These main neural circuits are glutamatergic and glutamate is a key neurotransmitter for memory.

Changes in both presynaptic and postsynaptic strength, i.e., synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD), have been extensively studied in glutamatergic synapses of the hippocampus.^4,5) Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are dynamically linked with the influx of extracellular Zn²⁺ and intracellular Zn²⁺ signaling plays a key role for cognitive performance and memory as well as intracellular Ca²⁺ signaling.^6,7) However, glutamate receptor activation by excess extracellular glutamate induces glutamate excitotoxicity^8,9) and leads to a common pathway for neuronal death.^10,11) Hippocampal CA1 pyramidal cells are the most susceptible to neuronal death in the hippocampus after stroke/ischemia. CA1 pyramidal cell death is due to extracellular Zn²⁺ influx into postsynaptic neurons through Ca²⁺-permeable AMPA receptors, which is dynamically linked with Zn²⁺ release from zincergic Shaffer collaterals, a subclass of glutamatergic fibers, which concentrates zinc in the presynaptic vesicles.^12–16) Approximately 50% of the Shaffer collaterals are zincergic. On the other hand, it has been reported that the dentate gyrus is vulnerable to aging in the hippocampus.²⁾

Alzheimer’s disease (AD), a progressive neurological disease, is the most common cause of dementia in elderly people.¹⁷⁾ In AD, pathogenic progression may last for 20–30 years before clinical onset. Individuals with mild cognitive impairment (MCI) have approximately 30% fewer neurons in the entorhinal cortex and show synaptic loss to the dentate gyrus, which correlates with cognitive impairment.^18–20) This cellular disconnection in the dentate gyrus suggests that this region is one of the earliest sites to show synaptic dysfunction.²¹⁾ In postmortem studies, it is reported that the hippocampus and entorhinal cortex may be the first brain regions to be affected in AD.²²⁾ Amyloid-β (Aβ) is the major component of neuritic senile plaques in AD brain and is a causative candidate for AD pathogenesis.

Interestingly, extracellular Zn²⁺ influx into hippocampal neurons is increased by not only glutamatergic synapse excitation^23,24) but also extracellular Aβ_1–42.²⁵⁾ Glutamatergic synapse excitation rapidly increases intracellular Zn²⁺ through Ca²⁺-permeable AMPA receptors followed by cognitive decline. The formation of Zn–Aβ_1–42 in the extracellular compartment also rapidly increases intracellular Zn²⁺ followed by Aβ_1–42-induced cognitive decline. The evidence indicates that modification of extracellular Zn²⁺ dynamics, which is linked with age-related changes, is critical for cognitive decline. It is estimated that the dentate gyrus is vulnerable to this modification. The present paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ_1–42 neurotoxicity.

2. PHYSIOLOGY OF HIPPOCAMPAL ZN²⁺ IN SYNAPTIC PLASTICITY

Zn²⁺ concentration in the brain extracellular fluid, which is estimated to be approximately 10 nM in adults,²⁶⁾ is much lower than Ca²⁺ concentration (ca. 1.3 mM). Thus much less attention has been paid to essentiality of Zn²⁺ in brain extracellular fluid for synaptic neurotransmission. Artificial cerebrospinal fluid (ACSF), i.e., brain extracellular medium, without Zn²⁺ has been widely used for in vitro and in vivo experiments. However, synaptic neurotransmission including not only neuronal excitation but also synaptic plasticity such as LTP is modified in brain slices bathed in ACSF without Zn²⁺.²⁷⁾ Extracellular Zn²⁺ in the range of physiological concentrations is important to understand synaptic function precisely. Low nanomolar concentrations of Zn²⁺ are physiologically relevant, compared with micromolar concentrations of Zn²⁺ widely used, which are often neurotoxic.²⁸⁾

Spontaneous presynaptic activity in the stratum lucidum where zincergic mossy fibers are contained is suppressed in brain slices from young rats bathed in ACSF containing 10 nM Zn²⁺, indicating that extracellular Zn²⁺ suppressively modulates hippocampal presynaptic activity.²⁹⁾ Micromolar Zn²⁺ also suppresses hippocampal mossy fiber exocytosis.³⁰⁾ It is likely that Zn²⁺ dose-dependently suppresses presynaptic activity in the hippocampus. To examine the in vivo action of 10 nM Zn²⁺ on LTP, furthermore, the recording region is perfused using a recording electrode attached to a microdialysis probe. The magnitude of LTP at medial perforant pathway-dentate granule cell synapses is not significantly modified in young rats under perfusion with ACSF containing 10 nM ZnCl₂, compared to perfusion with ACSF without Zn²⁺. Interestingly, the magnitude of LTP is attenuated in young rats under perfusion with ACSF containing 100 nM ZnCl₂, whereas it is not modified in aged rats. In aged rats, the magnitude of LTP is enhanced under perfusion with ACSF containing 10 mM Ca-ethylenediaminetetraacetic acid (CaEDTA), an extracellular Zn²⁺ chelator. The findings suggest that the basal levels of extracellular Zn²⁺, which are the range of low nanomolar concentrations (ca. 10 nM), are age-dependently increased in the aged dentate gyrus and negatively modulate LTP.²⁹⁾ The finding that extracellular zinc concentration in the hippocampus determined by hippocampal perfusion using the microdialysis technique is increased age-dependently supports this idea.³¹⁾ It is likely that the basal level of extracellular Zn²⁺ physiologically reaches approximately 100 nM in aged rats.

It is reported that zinc concentration in CSF is in the range 150–380 nM.^32–34) If it is the same as zinc concentration in the brain extracellular fluid, a large portion of zinc is not free ion in the brain extracellular fluid under the basal (static) condition. At zincergic synapses such as Shaffer collateral and mossy fiber synapses, extracellular Zn²⁺ levels are dynamically modified by the degree of activity-dependent Zn²⁺ release, which is required for learning and memory via synaptic plasticity as described below.^6,7) ZnAF-2DA, a membrane-permeable Zn²⁺ indicator, is a useful tool for examining the direct involvement of synaptic Zn²⁺ in cognitive function. ZnAF-2DA is taken up into cells through the cell membrane and is hydrolyzed by esterase in the cytosol followed by the production of ZnAF-2, which cannot permeate the cell membrane.^35,36) When ZnAF-2DA is locally injected into the hippocampus, ZnAF-2 (K_d, 2.7 nM for Zn²⁺) taken up into neurons blocks cellular transient changes in Zn²⁺ concentration, i.e., intracellular Zn²⁺ signaling only in the injected area.

The concurrent tests of in vivo LTP and learning behavior in separated experiments using ZnAF-2DA indicates essentiality of synaptic Zn²⁺ for cognition; the influx of extracellular Zn²⁺ into CA1 pyramidal cells, which is linked to Zn²⁺ release form the Schaffer collaterals, is required for object recognition memory via in vivo Schaffer collateral LTP.⁶⁾ On the other hand, glutamatergic input to CA1 pyramidal cells via the medial perforant pathway (the temporoammonic pathway) from the entorhinal cortex facilitates memory consolidation and is required for temporal association memory and spatial working memory.^37–39) Although the medial perforant pathway from the entorhinal cortex is non-zincergic,⁴⁰⁾ intracellular Zn²⁺ signaling, which originates in internal stores/proteins, is involved in LTP at medial perforant pathway-CA1 pyramidal cell synapses.⁷⁾ Cellular transient changes in Zn²⁺ concentration from both extracellular and intracellular compartments function in CA1 pyramidal cells.

In dentate granule cells, which are innervated by the non-zincergic medial perforant pathway, intracellular Zn²⁺ signaling, which also originates in internal stores/proteins, is involved in object recognition memory via LTP at medial perforant pathway-dentate granule cells synapses.⁴¹⁾ LTP maintenance underlies memory retention. The mechanism maintaining medial perforant pathway LTP also requires intracellular Zn²⁺ signaling in dentate granule cells, which is involved in the formation of F-actin, and retains space recognition memory.⁴²⁾ It is reported that the basal concentration of intracellular (cytosol) Zn²⁺ is less than 1 nM.^43,44) Cellular transient changes in Zn²⁺ concentration are used as a marker for plastic changes in synapse function and structure induced by learning and cognitive performance. Intracellular Zn²⁺ levels can transiently reach a few nanomolar concentrations after LTP induction, while the changes in intracellular Zn²⁺ level remain unclear in the process of LTP maintenance. LTP maintenance at medial perforant pathway-dentate granule cell synapses is affected by blocking intracellular Zn²⁺ signaling with ZnAF-2DA.^42,45) Zn²⁺ seems to be required for enlarging synapse structure and also maintaining the enlargement.⁴⁶⁾

3. MODIFICATION OF EXTRACELLULAR ZN²⁺ DYNAMICS AND ITS RELATIONSHIP TO Aβ NEUROTOXICITY

New neurons are generated from neural stem/progenitor cells in the subgranular zone of the dentate gyrus throughout life. As aging progresses, the rate of neurogenesis decreases exponentially, which might be responsible for age-related cognitive decline in humans and animals.^47,48) Because neurogenesis-related apoptosis also occurs in the subgranular zone, the apoptosis is likely to be significantly increased along with aging. It is possible that the apoptosis is involved in the vulnerability of the dentate gyrus to aging, which might be linked with cognitive decline.⁴⁹⁾ The apoptosis locally elevates extracellular K⁺ concentration in the subgranular zone and the elevation is due to the efflux of intracellular K⁺ (approximately 140 mM) by disruption of cell membranes. The elevation of extracellular K⁺ concentration can non-specifically excite granule cells, which exist nearby in the dentate gyrus, followed by rapid increase in extracellular Zn²⁺ influx via excess glutamate signaling. Both memory acquisition via LTP induction and memory retention via LTP maintenance are affected after local injection of high K⁺ into the dentate gyrus, which rapidly increases intracellular Zn²⁺ in dentate granule cells through Ca²⁺-permeable AMPA receptors.^24,50) Although high K⁺-induced Zn²⁺ influx also affects memory acquisition via LTP induction in the hippocampal CA1,²³⁾ neurogenesis-related apoptosis, which can be a cause of cognitive decline, may be involved in age-related modification of dentate gyrus function, in addition to the decreased neurogenesis.

Synaptic activity dynamically regulates extracellular Aβ levels in the brain. Extracellular Aβ levels are directly linked with synaptic vesicle exocytosis. Aβ release from synaptic vesicle is linked with dynamic changes in extracellular Aβ levels, which are independent of changes in APP processing.⁵¹⁾ In normal young animal experiments, endogenous Aβ is involved in learning and memory and endogenous Aβ_1–42 supports LTP expression.^52,53) It is likely that Aβ_1–42 supports LTP and memory at picomolar concentrations under physiological conditions, while it affects them at pathological nanomolar concentrations.^54,55) Interestingly, intracellular Zn²⁺ dysregulation, which is a cause of cognitive decline, is induced by extracellular Aβ_1–42, as well as excess extracellular glutamate. Because Zn²⁺ readily induces toxic Aβ oligomerization, this metal ion has been implicated in AD pathogenesis.^56–58) Aβ is bound to Zn²⁺ via histidine residues and the K_d values of Zn²⁺ to Aβ_1–40 are in the range 0.1–60 µM.⁵⁹⁾ However, the K_d value of Zn²⁺ to Aβ_1–42 is unreported. It is estimated that, as is the case with Cu²⁺ binding to Aβ,⁶⁰⁾ the apparent K_d of metal binding to Aβ_1–42 is higher in affinity than that to Aβ_1–40 probably due to the disturbed equilibrium caused by the enhanced self-assembly of Aβ_1–42 oligomers.

Short-term memory loss emerges in normal elderly people and pathologically increases in the pre-dementia stage of AD. In young rats, in vivo perforant pathway LTP is unaffected even under perfusion with 1000 nM Aβ_1–42 in ACSF without Zn²⁺, while it is attenuated under pre-perfusion with 5 nM Aβ_1–42 in ACSF containing 10 nM Zn²⁺, suggesting that Aβ_1–42-induced attenuation of LTP is extracellular Zn²⁺-dependent.⁶¹⁾ When extracellular Aβ_1–42 concentration reaches 500 pM in the dentate gyrus, Zn–Aβ_1–42 is rapidly formed in the extracellular compartment and taken up into dentate granule cells (Fig. 1). The rapid uptake of both Aβ_1–42 and Zn²⁺ is blocked by CaEDTA and by Cd²⁺, a metal that displaces Zn²⁺ for Aβ_1–42-binding. Local injection of Aβ_1–42 into the dentate granule cell layer of young rats induces rapid memory disturbance that is rescued by co-injection of Zn²⁺ chelators and CdCl₂.^25,61) Therefore once ferried by Aβ_1–42 into dentate granule cells, the Zn²⁺ cargo is released from Aβ_1–42 in dentate granule cells. Aβ_1–42-mediated cognitive decline may be induced by the intrusion of Aβ, Zn²⁺, or both together into the normal dentate granule cells⁶¹⁾ (Fig. 1). The in vivo rapid action of picomolar Aβ_1–42 with extracellular Zn²⁺ in the dentate gyrus suggests that Zn²⁺ has a high affinity for Aβ_1–42 (in vivo K_d value of Zn²⁺ to Aβ_1–42, approximately 3–30 nM) and that dentate granule cells are vulnerable to Zn–Aβ_1–42 neurotoxicity. On the other hand, Aβ_1–40 and Zn²⁺ are not taken up into dentate granule cells, consistent with lower affinity of Aβ_1–40 for Zn²⁺ than Aβ_1–42.⁶¹⁾ Blocking the formation of Zn–Aβ_1–42 in the extracellular compartment may be effective for preventing Aβ_1–42-mediated cognitive decline (Fig. 1).

Fig. 1. A Model for Neuronal Intoxication by Zn–Aβ_1–42 Complexes

Dentate granule neurons only take up Aβ_1–42 when the peptide is bound to Zn²⁺, whereupon Zn–Aβ_1–42 complexes enter dentate granule neurons and either the complexes or the liberated Zn²⁺ induces cognitive decline. Cd²⁺ can displace Zn²⁺ from Aβ_1–42 and prevent it from being taken up into dentate granule neurons, neutralizing its neurotoxicity. Zn²⁺ is withdrawn into peptide complexes more readily by oligomers. Aβ_1–42 more rapidly forms oligomers and fosters neuronal uptake more readily than Aβ_1–40.⁶²⁾ (Color figure can be accessed in the online version.)

4. WEAKENED INTRACELLULAR ZN²⁺-BUFFERING IN THE DENTATE GYRUS

It has been reported that weakened intracellular Ca²⁺-buffering, a net decrease in the Ca²⁺-buffering capacity is linked with not only aging but also neurological diseases such as AD.^62,63) Judging from the estimated elevation of extracellular Zn²⁺ concentration and enhancement of extracellular Zn²⁺ influx in aged rats,^29,31) it is possible that intracellular Zn²⁺-buffering is modified in aged rats. High K⁺-induced increase in extracellular Zn²⁺ influx into dentate granule cells is enhanced in aged rats, followed by both attenuations of LTP induction and maintained LTP at medial perforant pathway-dentate granule cell synapses, suggesting that the aged dentate gyrus is vulnerable to cognitive decline associated with intracellular Zn²⁺ dysregulation.^31,45) Glutamate receptor 2 (GluR2)-lacking Ca²⁺-permeable AMPA receptors play a key role for not only Zn²⁺-mediated neuronal death in the hippocampal CA1,^64,65) but also Zn²⁺-mediated cognitive decline.^31,45) In the hippocampus, levels of mRNA encoding GluR1 and GluR2 are highest in the dentate gyrus and the GluR1/GluR2 mRNA ratios are increased along with aging.⁶⁶⁾ Influx of extracellular Zn²⁺ through Ca²⁺-permeable AMPA receptors may be involved in age-related cognitive decline associated with intracellular Zn²⁺ dysregulation^31,45) (Fig. 2).

Fig. 2. Intracellular Zn²⁺-Buffering Is Weakened in the Aged Dentate Gyrus

Intracellular Zn²⁺-buffering is weakened at medial perforant pathway (MPP)-dentate granule cell synapses of the aged dentate gyrus⁴⁶⁾ and may be linked with vulnerability to cognitive decline. Zn–Aβ_1–42-induced cognitive decline might more readily emerge because of weakened intracellular Zn²⁺-buffering in the normal aged dentate gyrus. CC, Ca²⁺ channel; ZIP, zinc import protein. (Color figure can be accessed in the online version.)

When ZnAF-2DA is locally injected into the dentate gyrus, interestingly, the Zn²⁺-binding capacity of intracellular ZnAF-2, which is assessed by changes in fluorescence intensity, is more rapidly lost in the aged dentate molecular layer where medial perforant pathway-dentate granule cell synapses are contained than in the young dentate molecular layer. The data suggest that intracellular Zn²⁺-buffering capacity is decreased in the aged dentate gyrus⁴⁵⁾ (Fig. 2). Characteristics (easiness) of extracellular Zn²⁺ influx may be linked with decreased intracellular Zn²⁺-buffering capacity in the aged dentate gyrus.⁴⁵⁾ The intracellular Zn²⁺-buffering system remains unclear and Ca²⁺-permeable channels, Zn²⁺ transporters (ZIP and ZnT), Zn²⁺-binding proteins such as metallothioneins, and internal stores containing Zn²⁺ may construct the Zn²⁺-buffering system. The vulnerability of the dentate gyrus to aging and Aβ_1–42 neurotoxicity seems to be linked with age-related modification of extracellular Zn²⁺ dynamics, which is induced with glutamate and Aβ_1–42 in the extracellular compartment (Fig. 2).

5. PERSPECTIVE

Intracellular Zn²⁺-buffering is weakened in the dentate gyrus along with aging, probably due to easiness of extracellular Zn²⁺ influx into dentate granule cells (Fig. 2), which increases vulnerability to cognitive decline. Aβ_1–42-induced cognitive decline, which is extracellular Zn²⁺-dependent, is due to increase in Zn²⁺ released from Aβ_1–42 in dentate granule cells (Fig. 1). Intracellular Zn²⁺-buffering may be also weakened by formation of Zn–Aβ_1–42 in the extracellular compartment (Fig. 2). To find out a strategy for preventing Aβ_1–42-mediated cognitive decline, therefore, it is important to understand the relation between age-related modifications of extracellular Zn²⁺ dynamics and the Zn²⁺-buffering system.

Conflict of Interest

The authors declare no conflict of interest.

REFERENCES

• 1) Knierim JJ. The hippocampus. Curr. Biol., 25, R1116–R1121 (2015).
• 2) Small SA, Schobel SA, Buxton RB, Witter MP, Barnes CA. A pathophysiological framework of hippocampal dysfunction in ageing and disease. Nat. Rev. Neurosci., 12, 585–601 (2011).
• 3) Sasaki T, Leutgeb S, Leutgeb JK. Spatial and memory circuits in the medial entorhinal cortex. Curr. Opin. Neurobiol., 32, 16–23 (2015).
• 4) Malenka RC, Nicoll RA. Long-term potentiation—a decade of progress? Science, 285, 1870–1874 (1999).
• 5) Blitzer RD, Iyengar R, Landau EM. Postsynaptic signaling networks: cellular cogwheels underlying long-term plasticity. Biol. Psychiatry, 57, 113–119 (2005).
• 6) Takeda A, Suzuki M, Tempaku M, Ohashi K, Tamano H. Influx of extracellular Zn²⁺ into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation. Neuroscience, 304, 209–216 (2015).
• 7) Tamano H, Nishio R, Takeda A. Involvement of intracellular Zn²⁺ signaling in LTP at perforant pathway-CA1 pyramidal cell synapse. Hippocampus, 27, 777–783 (2017).
• 8) Danbolt NC. Glutamate uptake. Prog. Neurobiol., 65, 1–105 (2001).
• 9) Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol. Sin., 30, 379–387 (2009).
• 10) Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog. Neurobiol., 115, 157–188 (2014).
• 11) Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front. Neurosci., 9, 469 (2015).
• 12) Colbourne F, Grooms SY, Zukin RS, Buchan AM, Bennett MV. Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Proc. Natl. Acad. Sci. U.S.A., 100, 2906–2910 (2003).
• 13) Frederickson CJ, Koh JY, Bush AI. The neurobiology of zinc in health and disease. Nat. Rev. Neurosci., 6, 449–462 (2005).
• 14) Noh KM, Yokota H, Mashiko T, Castillo PE, Zukin RS, Bennett MV. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death. Proc. Natl. Acad. Sci. U.S.A., 102, 12230–12235 (2005).
• 15) Stork CJ, Li YV. Rising zinc: a significant cause of ischemic neuronal death in the CA1 region of rat hippocampus. J. Cereb. Blood Flow Metab., 29, 1399–1408 (2009).
• 16) Sensi SL, Paoletti P, Bush AI, Sekler I. Zinc in the physiology and pathology of the CNS. Nat. Rev. Neurosci., 10, 780–791 (2009).
• 17) Querfurth HW, LaFerla FM. Alzheimer’s disease. N. Engl. J. Med., 362, 329–344 (2010).
• 18) Gómez-Isla T, Price JL, McKeel DW Jr, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J. Neurosci., 16, 4491–4500 (1996).
• 19) Scheff SW, Price DA, Schmitt FA, Mufson EJ. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol. Aging, 27, 1372–1384 (2006).
• 20) Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum. Mol. Genet., 19 (R1), R12–R20 (2010).
• 21) Brouillette J, Caillierez R, Zommer N, Alves-Pires C, Benilova I, Blum D, De Strooper B, Buée L. Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-β1–42 oligomers are revealed in vivo by using a novel animal model. J. Neurosci., 32, 7852–7861 (2012).
• 22) Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science, 225, 1168–1170 (1984).
• 23) Takeda A, Takada S, Nakamura M, Suzuki M, Tamano H, Ando M, Oku N. Transient increase in Zn²⁺ in hippocampal CA1 pyramidal neurons causes reversible memory deficit. PLoS ONE, 6, e28615 (2011).
• 24) Suzuki M, Fujise Y, Tsuchiya Y, Tamano H, Takeda A. Excess influx of Zn²⁺ into dentate granule cells affects object recognition memory via attenuated LTP. Neurochem. Int., 87, 60–65 (2015).
• 25) Takeda A, Nakamura M, Fujii H, Uematsu C, Minamino T, Adlard PA, Bush AI, Tamano H. Amyloid β-mediated Zn²⁺ influx into dentate granule cells transiently induces a short-term cognitive deficit. PLOS ONE, 9, e115923 (2014).
• 26) Frederickson CJ, Giblin LJ, Krezel A, McAdoo DJ, Muelle RN, Zeng Y, Balaji RV, Masalha R, Thompson RB, Fierke CA, Sarvey JM, Valdenebro M, Prough DS, Zornow MH. Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion. Exp. Neurol., 198, 285–293 (2006).
• 27) Takeda A, Tamano H. Significance of low nanomolar concentration of Zn²⁺ in artificial cerebrospinal fluid. Mol. Neurobiol., 54, 2477–2482 (2017).
• 28) Takeda A, Tamano H. Insight into cognitive decline from Zn²⁺ dynamics through extracellular signaling of glutamate and glucocorticoids. Arch. Biochem. Biophys., 611, 93–99 (2016).
• 29) Tamano H, Nishio R, Shakushi Y, Sasaki M, Koike Y, Osawa M, Takeda A. In vitro and in vivo physiology of low nanomolar concentrations of Zn²⁺ in artificial cerebrospinal fluid. Sci. Rep., 7, 42897 (2017).
• 30) Minami A, Sakurada N, Fuke S, Kikuchi K, Nagano T, Oku N, Takeda A. Inhibition of presynaptic activity by zinc released from mossy fiber terminals during tetanic stimulation. J. Neurosci. Res., 83, 167–176 (2006).
• 31) Takeda A, Koike Y, Osawa M, Tamano H. Characteristic of extracellular Zn²⁺ influx in the middle-aged dentate gyrus and its involvement in attenuation of LTP. Mol. Neurobiol., 55, 2185–2195 (2018).
• 32) Hershey CO, Hershey LA, Varnes A, Vibhakar SD, Lavin P, Strain WH. Cerebrospinal fluid trace element content in dementia: clinical, radiologic, and pathologic correlations. Neurology, 33, 1350–1353 (1983).
• 33) Gellein K, Skogholt JH, Aaseth J, Thoresen GB, Lierhagen S, Steinnes E, Syversen T, Flaten TP. Trace elements in cerebrospinal fluid and blood from patients with a rare progressive central and peripheral demyelinating disease. J. Neurol. Sci., 266, 70–78 (2008).
• 34) Michalke B, Nischwitz V. Review on metal speciation analysis in cerebrospinal fluid-current methods and results: a review. Anal. Chim. Acta, 682, 23–36 (2010).
• 35) Hirano T, Kikuchi K, Urano Y, Nagano T. Improvement and biological applications of fluorescent probes for zinc, ZnAFs. J. Am. Chem. Soc., 124, 6555–6562 (2002).
• 36) Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, Nishiyama N, Nagano T, Matsuki N, Ikegaya Y. Mossy fiber Zn²⁺ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippocampal CA3 circuits. J. Cell Biol., 158, 215–220 (2002).
• 37) Remondes M, Schuman EM. Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature, 431, 699–703 (2004).
• 38) Suh J, Rivest AJ, Nakashiba T, Tominaga T, Tonegawa S. Entorhinal cortex layer III input to the hippocampus is crucial for temporal association memory. Science, 334, 1415–1420 (2011).
• 39) Vago DR, Kesner RP. Disruption of the direct perforant path input to the CA1 subregion of the dorsal hippocampus interferes with spatial working memory and novelty detection. Behav. Brain Res., 189, 273–283 (2008).
• 40) Sindreu CB, Varoqui H, Erickson JD, Pérez-Clausell J. Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus. Cereb. Cortex, 13, 823–829 (2003).
• 41) Takeda A, Tamano H, Ogawa T, Takada S, Nakamura M, Fujii H, Ando M. Intracellular Zn²⁺ signaling in the dentate gyrus is required for object recognition memory. Hippocampus, 24, 1404–1412 (2014).
• 42) Tamano H, Minamino T, Fujii H, Takada S, Nakamura M, Ando M, Takeda A. Blockade of intracellular Zn²⁺ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP. Hippocampus, 25, 952–962 (2015).
• 43) Sensi SL, Canzoniero LMT, Yu SP, Ying HS, Koh JY, Kerchner GA, Choi DW. Measurement of intracellular free zinc in living cortical neurons: routes of entry. J. Neurosci., 17, 9554–9564 (1997).
• 44) Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, Kikuchi K, Holmes WR. Insights into Zn²⁺ homeostasis in neurons from experimental and modeling studies. Am. J. Physiol. Cell Physiol., 294, C726–C742 (2008).
• 45) Takeda A, Tamano H, Murakami T, Nakada H, Minamino T, Koike Y. Weakened intracellular Zn²⁺-buffering in the aged dentate gyrus and its involvement in erasure of maintained LTP. Mol. Neurobiol., 55, 3856–3865 (2018).
• 46) Grabrucker AM, Knight MJ, Proepper C, Bockmann J, Joubert M, Rowan M, Nienhaus GU, Garner CC, Bowie JU, Kreutz MR, Gundelfinger ED, Boeckers TM. Concerted action of zinc and ProSAP/Shank in synaptogenesis and synapse maturation. EMBO J., 30, 569–581 (2011).
• 47) Aizawa K, Ageyama N, Terao K, Hisatsune T. Primate-specific alterations in neural stem/progenitor cells in the aged hippocampus. Neurobiol. Aging, 32, 140–150 (2011).
• 48) Jinno S. Aging affects new cell production in the adult hippocampus: A quantitative anatomic review. J. Chem. Neuroanat., pii: S0891-0618(15)00094-0 (2015).
• 49) Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, Small SA. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat. Neurosci., 17, 1798–1803 (2014).
• 50) Takeda A, Tamano H, Hisatsune M, Murakami T, Nakada H, Fujii H. Maintained LTP and memory are lost by Zn²⁺ influx into dentate granule cells, but not Ca²⁺ influx. Mol. Neurobiol., 55, 1498–1508 (2018).
• 51) Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron, 48, 913–922 (2005).
• 52) Morley JE, Farr SA, Banks WA, Johnson SN, Yamada KA, Xu L. A physiological role for amyloid beta protein: enhancement of learning and memory. J. Alzheimer’s Dis., 19, 441–449 (2010).
• 53) Puzzo D, Privitera L, Fa’ M, Staniszewski A, Hashimoto G, Aziz F, Sakurai M, Ribe EM, Troy CM, Mercken M, Jung SS, Palmeri A, Arancio O. Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory. Ann. Neurol., 69, 819–830 (2011).
• 54) Rammes G, Hasenjäger A, Sroka-Saidi K, Deussing JM, Parsons CG. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology, 60, 982–990 (2011).
• 55) Puzzo D, Privitera L, Palmeri A. Hormetic effect of amyloid-β peptide in synaptic plasticity and memory. Neurobiol. Aging, 33, 1484.e15–1484.e24 (2012).
• 56) Bush AI, Pettingell WH, Multhaup G, d Paradis M, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science, 265, 1464–1467 (1994).
• 57) Bush AI. The metal theory of Alzheimer’s disease. J. Alzheimer’s Dis., 33 (Suppl. 1), S277–S281 (2013).
• 58) Ayton S, Lei P, Bush AI. Metallostasis in Alzheimer’s disease. Free Radic. Biol. Med., 62, 76–89 (2013).
• 59) Tõugu V, Karafin A, Palumaa P. Binding of zinc(II) and copper(II) to the full-length Alzheimer’s amyloid-beta peptide. J. Neurochem., 104, 1249–1259 (2008).
• 60) Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI. Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1–42. J. Neurochem., 75, 1219–1233 (2000).
• 61) Takeda A, Tamano H, Tempaku M, Sasaki M, Uematsu C, Sato S, Kanazawa H, Datki ZL, Adlard PA, Bush AI. Extracellular Zn²⁺ is essential for amyloid β_1–42-induced cognitive decline in the normal brain and its rescu. J. Neurosci., 37, 7253–7262 (2017).
• 62) Kumar A, Bodhinathan K, Foster TC. Susceptibility to calcium dysregulation during brain aging. Front. Aging Neurosci., 1, 2 (2009).
• 63) Berridge MJ. Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia. Prion, 7, 2–13 (2013).
• 64) Liu S, Lau L, Wei J, Zhu D, Zou S, Sun HS, Fu Y, Liu F, Lu Y. Expression of Ca²⁺-permeable AMPA receptor channels primes cell death in transient forebrain ischemia. Neuron, 43, 43–55 (2004).
• 65) Weiss JH. Ca permeable AMPA channels in diseases of the nervous system. Front. Mol. Neurosci., 4, 42 (2011).
• 66) Pagliusi SR, Gerrard P, Abdallah M, Talabot D, Catsicas S. Age-related changes in expression of AMPA-selective glutamate receptor subunits: is calcium-permeability altered in hippocampal neurons? Neuroscience, 61, 429–433 (1994).