Extracellular Zn2+ Is Essential for Amyloid β1–42-Induced Cognitive Decline in the Normal Brain and Its Rescue

Takeda, Atsüshi; Tamano, Haruna; Tempaku, Munekazu; Sasaki, Masaru; Uematsu, Chihiro; Sato, Shoko; Kanazawa, Hiroaki; Datki, Zsolt; Adlard, Paul A.; Bush, Ashley I.

doi:10.1523/jneurosci.0954-17.2017

Cited by 48 publications

(38 citation statements)

References 45 publications

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“…Our results demonstrate that the

C_{{Zn}^{2+}}^{ex}

surrounding overexcited neurons can reach ≥100 × 10 −9 m , which is enough for the binding of Zn 2+ to the high affinity site of Aβ. Recently, Takeda et al showed that treating the dentate granule cells in a rat hippocampal slice with 5 × 10 −9 m of Aβ (1–42) in the presence of 10 × 10 −9 m of Zn 2+ , but not Cd 2+ , Fe 3+ , or Cu 2+ , could attenuate the long‐term potentiation . Therefore, the Zn 2+ coreleased with glutamate must be under strict regulation to avoid the formation of Aβ‐Zn 2+ complexes.…”

Section: Resultsmentioning

confidence: 99%

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

Anand

Chi

Banerjee

et al. 2018

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The Zn2+ stored in the secretory vesicles of glutamatergic neurons is coreleased with glutamate upon stimulation, resulting in the elevation of extracellular Zn2+ concentration (CZn2+ex). This elevation of CZn2+ex regulates the neurotransmission and facilitates the fibrilization of amyloid‐β (Aβ). However, the exact CZn2+ex surrounding neurons under (patho)physiological conditions is not clear and the connection between CZn2+ex and the Aβ fibrilization remains obscure. Here, a silicon nanowire field‐effect transistor (SiNW‐FET) with the Zn2+‐sensitive fluorophore, FluoZin‐3 (FZ‐3), to quantify the CZn2+ex in real time is modified. This FZ‐3/SiNW‐FET device has a dissociation constant of ≈12 × 10−9m against Zn2+. By placing a coverslip seeded with cultured embryonic cortical neurons atop an FZ‐3/SiNW‐FET, the CZn2+ex elevated to ≈110 × 10−9m upon stimulation with α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA). Blockers against the AMPA receptor or exocytosis greatly suppress this elevation, indicating that the Zn2+ stored in the synaptic vesicles is the major source responsible for this elevation of CZn2+ex. In addition, a SiNW‐FET modified with Aβ could bind Zn2+ with a dissociation constant of ≈633 × 10−9m and respond to the Zn2+ released from AMPA‐stimulated neurons. Therefore, the CZn2+ex can reach a level high enough to bind Aβ and the Zn2+ homeostasis can be a therapeutic strategy to prevent neurodegeneration.

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“…Our results demonstrate that the

C_{{Zn}^{2+}}^{ex}

Section: Resultsmentioning

confidence: 99%

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

Anand

Chi

Banerjee

et al. 2018

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“…It was reported that the dentate gyrus is vulnerable to aging and AD in the hippocampal formation. 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)…”

Section: Modification Of Intracellular Zn 2+ Buffering With Agingmentioning

confidence: 99%

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

Tamano

Takeda

2019

Biological & Pharmaceutical Bulletin

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The basal concentrations of extracellular Zn 2 and intracellular Zn 2 , which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca 2 (1.3 mM) and intracellular Ca 2 (100 nM), respectively, resulting in much less attention paid to Zn 2 than to Ca 2. However, intracellular Zn 2 dysregulation, which is closely linked with glutamate-and amyloid β-mediated extracellular Zn 2 influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca 2 dysregulation. It is estimated that the age-dependent increase in the basal concentration of extracellular Zn 2 in the hippocampus plays a key role in cognitive decline and neurodegeneration. The characteristics of extracellular Zn 2 influx in the hippocampus may be modified age-dependently, probably followed by modification of intracellular Zn 2 buffering that is closely linked with age-related cognitive decline and neurodegeneration. Reduction of intracellular Zn 2-buffering capacity may be linked with the pathophysiology of progressive neurodegeneration such as Alzheimer's disease. This paper deals with age-dependent modification of intracellular Zn 2 buffering in the hippocampus and its impact. On the basis of the estimated impact, we propose a potential defense strategy against Zn 2-mediated neurodegeneration, i.e., metallothionein induction in the hippocampus.

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“…The rapid uptake of both Aβ into the dentate granule cell layer of young rats induces rapid memory disturbance that is rescued by co-injection of Zn 2+ chelators and CdCl 2 . 25,61) Therefore once ferried by Aβ 1-42 into dentate granule cells, the Zn 2+ 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, Zn 2+ , or both together into the normal dentate granule cells 61) (Fig.…”

Section: Modification Of Extracellular Zn 2+ Dy-namics and Its Relatimentioning

confidence: 99%

“…25,61) Therefore once ferried by Aβ 1-42 into dentate granule cells, the Zn 2+ 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, Zn 2+ , or both together into the normal dentate granule cells 61) (Fig. 1) increase in extracellular Zn 2+ 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 Zn 2+ dysregulation.…”

Section: Modification Of Extracellular Zn 2+ Dy-namics and Its Relatimentioning

confidence: 99%

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β1–42 Neurotoxicity Linked with Modified Extracellular Zn2+ Dynamics?

Takeda

Tamano

2018

Biological & Pharmaceutical Bulletin

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The basal levels of extracellular Zn 2 are in the range of low nanomolar concentrations in the hippocampus and perhaps increase age-dependently. Extracellular Zn 2 dynamics is critical for cognitive activity and excess influx of extracellular Zn 2 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 Zn 2 influx into dentate granule cells via high K -induced perforant pathway excitation leads to cognitive decline. Modified extracellular Zn 2 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 Zn 2 released from Aβ 1-42 , suggesting that dentate granule cells are sensitive to extracellular Zn 2 -dependent Aβ 1-42 toxicity. This paper deals with proposed vulnerability of the dentate gyrus to aging and Aβ 1-42 neurotoxicity.

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Extracellular Zn²⁺ Is Essential for Amyloid β_1–42-Induced Cognitive Decline in the Normal Brain and Its Rescue

Cited by 48 publications

References 45 publications

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

Age-Dependent Modification of Intracellular Zn<sup>2+</sup> Buffering in the Hippocampus and Its Impact

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β<sub>1–42</sub> Neurotoxicity Linked with Modified Extracellular Zn<sup>2+</sup> Dynamics?

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Extracellular Zn2+ Is Essential for Amyloid β1–42-Induced Cognitive Decline in the Normal Brain and Its Rescue

Cited by 48 publications

References 45 publications

The Extracellular Zn2+ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

The Extracellular Zn2+ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

Age-Dependent Modification of Intracellular Zn<sup>2+</sup> Buffering in the Hippocampus and Its Impact

Is Vulnerability of the Dentate Gyrus to Aging and Amyloid-β<sub>1–42</sub> Neurotoxicity Linked with Modified Extracellular Zn<sup>2+</sup> Dynamics?

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Extracellular Zn²⁺ Is Essential for Amyloid β_1–42-Induced Cognitive Decline in the Normal Brain and Its Rescue

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor

The Extracellular Zn²⁺ Concentration Surrounding Excited Neurons Is High Enough to Bind Amyloid‐β Revealed by a Nanowire Transistor