Difference in ability for extracellular Zn2+ influx between human and rat amyloid β1-42 and its significance

doi:10.1016/j.neuro.2019.01.005

NeuroToxicology

Volume 72, May 2019, Pages 1-5

https://doi.org/10.1016/j.neuro.2019.01.005 Get rights and content

Highlights

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Rat Aβ_1–42 has lower affinity for extracellular Zn²⁺ than human Aβ_1–42.
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Rat Aβ_1–42 does not capture extracellular Zn²⁺.
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Rat Aβ_1–42 has no significant effect on LTP at 5 nM.
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Mice and rats are applicable to study of <1 nM human Aβ_1–42 synaptotoxicity.

Abstract

The accumulation of amyloid-β_1–42 (Aβ_1–42), a constituively-generated peptide, in the brain is considered an upstream event in pathogenesis of Alzheimer’s disease. Aβ_1–42-induced pathophysiology has been extensively studied in experimental mice and rats. However, neurotoxicity of murine Aβ_1–42 is much less understood than human Aβ_1–42. Here we report difference in ability for extracellular Zn²⁺ influx into dentate granule cells of rats between human and rat Aβ_1–42 and its significance. Human Aβ_1–42 rapidly increased intracellular Zn²⁺, which was determined with intracellular ZnAF-2, in dentate granule cells, 5 min after injection of Aβ_1–42 (25 μM, 1 μl) into the dentate gyrus, while rat Aβ_1–42 did not increase intracellular Zn²⁺. In vivo perforant pathway LTP was attenuated under pre-perfusion with 5 nM human Aβ_1–42 in artificial cerebrospinal fluid (ACSF) containing 10 nM Zn²⁺, recapitulating the concentration of extracellular Zn²⁺, but not with 5 nM rat Aβ_1–42 in ACSF containing 10 nM Zn²⁺. The present study suggests that rat Aβ_1–42 has lower affinity for extracellular Zn²⁺ than human Aβ_1–42 and does not capture Zn²⁺ in the extracellular compartment, resulting in no significant effect on cognitive activity of rat even in the range of very low nanomolar concentrations of endogenous Aβ_1–42.

Introduction

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia and has a preclinical phase of 20–30 years before clinical onset (Nestor et al., 2004; Querfurth and LaFerla, 2010). Amyloid-β (Aβ), a constituively-generated peptide, accumulation in the brain is the hallmark pathology of AD and is believed to play an upstream role in AD pathogenesis. Through mechanisms that are uncertain, endogenous Aβ can induce synapse dysfunction and contribute to cognitive decline in the pre-dementia stage of AD (Perrin et al., 2009a, b; Kepp, 2016).

Aβ is secreted into extracellular space after a sequential cleavage of amyloid precursor protein (APP) (Querfurth and LaFerla, 2010) and is normally produced in the brain, where the concentration has been estimated to be in the picomolar range in rodents (Cirrito et al., 2003). Aβ_1-40 and Aβ_1–42 are the two most abundant isoforms, and Aβ_1-40 is approximately 10 times as abundant as Aβ_1–42 in biological fluids (Schoonenboom et al., 2005). Importantly, Aβ_1–42 far more readily forms aggregates and is more neurotoxic than Aβ_1-40 (Mucke et al., 2000). Soluble Aβ_1–42 oligomers that are strong synaptotoxic molecules induce synaptic dysfunction and cognitive decline in AD (Walsh et al., 2002; Selkoe, 2008).

During the last few decades, transgenic mouse models have been developed for mimicing a range of AD-related pathologies. Although none of the models fully replicates the human disease, the models have been a key feature in translational research, providing important insights into the AD pathophysiology (Lithner et al., 2011). Transgenic rat models may offer distinctive advantages over mice. Rats are genetically, physiologically, and morphologically closer to humans. Importantly, the rat has a well-characterized, rich behavioral performance (Do Carmo and Cuello, 2013). On the other hand, much less attention has been paid to murine Aβ than human Aβ because mice and rats do not develop dementia and murine Aβ neurotoxicity is poorly understood. However, it is important to understand murine Aβ neurotoxicity when human Aβ neurotoxicity is evaluated in the normal mice and rats, especially in the range from high picomolar to very low nanomolar concentrations.

Zn²⁺ has been implicated in the AD pathogenesis by inducing human Aβ oligomerization (Bush et al., 1994; Bush, 2013; Adlard and Bush, 2018). We have been reported that human Aβ_1–42, unlike human Aβ_1-40, takes Zn²⁺ as a cargo into dentate granule cells in the normal rat brain, which causes cognitive decline via impairment of LTP induction (Takeda et al., 2014, 2017, 2018). Here we test whether rat Aβ_1–42 takes Zn²⁺ as a cargo into dentate granule cells, resulting in cognitive decline (Fig. 1).

Section snippets

Animals and chemicals

Male Wistar rats (7–9 weeks of age) were purchased from Japan SLC (Hamamatsu, Japan). Rats were housed under the standard laboratory conditions (23 ± 1 °C, 55 ± 5% humidity) and had access to tap water and food ad libitum. All the experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the University of Shizuoka that refer to the American Association for Laboratory Animals Science and the guidelines laid down by the NIH (NIH Guide for the Care

Results

Human Aβ_1–42 rapidly increases intracellular Zn²⁺ in dentate granule cells after injection of Aβ_1–42 (25 μM, 1 μl) into the dentate gyrus (Takeda et al., 2014). Aβ_1–42 captures Zn²⁺ in the extracellular compartment and both levels of Aβ_1–42 and Zn²⁺ are increased in dentate granule cells, resulting in cognitive decline via attenuated LTP. In contrast, human Aβ_1-40 does not increase intracellular Zn²⁺, probably because of no formation of a Zn-Aβ_1-40 complex in the extracellular compartment (

Discussion

Synaptic vesicle release may be the primary mediator of dynamic changes in extracellular Aβ levels, which are independent of changes in amyloid-β precursor protein (APP) processing, and is linked with synaptic activity (Cirrito et al., 2005). In normal young mice, endogenous Aβ_1–42 is involved in learning and memory via facilitating hippocampal LTP (Morley et al., 2010). Puzzo et al. (2011) report that both antirodent Aβ antibody and siRNA against murine APP attenuate LTP as well as contextual

Conflicts of interest

There are no conflicts to declare.

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Citation Excerpt :
Human Aβ1−40 and rat Aβ1–42 cannot capture extracellular Zn2+ in the brain extracellular compartment. Thus, Human Aβ1−40 and rat Aβ1–42 do not influence intracellular Zn2+ level in dentate granule cells after injection into the dentate granule cell layer (Tamano et al., 2019c; and 2019d). Human Aβ1−40- and rat Aβ1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol (Fig.7 and Fig. 8).
Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ_1–42-induced impairment of LTP is due to Aβ_1–42-mediated Zn²⁺ toxicity, we postulated that adrenergic β receptor activation reduces Aβ_1–42-mediated intracellular Zn²⁺ toxicity followed by rescuing Aβ_1–42 toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ_1–42 injection into the dentate granule cell layer. Human Aβ_1–42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic β receptor agonist, but not by co-injection of phenylephrine, an adrenergic α₁ receptor agonist. Isoproterenol did not reduce Aβ_1–42 uptake into dentate granule cells, but reduced increase in intracellular Zn²⁺ in dentate granule cells induced by Aβ_1–42. In contrast, phenylephrine did not reduce both Aβ_1–42 uptake and increase in intracellular Zn²⁺ by Aβ_1–42. In the case of human Aβ₁₋₄₀ and rat Aβ_1–42, which do not increase intracellular Zn²⁺, human Aβ₁₋₄₀- and rat Aβ_1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic β receptor activation reduces Aβ_1–42-mediated increase in intracellular Zn²⁺ in dentate granule cells, resulting in rescuing Aβ_1–42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aβ_1–42-induced cognitive decline that is caused by intracellular Zn²⁺ dysregulation in the hippocampus.
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To examine the relationship between cognitive decline via attenuated LTP and Aβ-mediated Zn2+ dynamics, human Aβ1-40 and rat Aβ1-42 (25 μM, 1 μl) is locally injected into the dentate gyrus in the same manner as reported previously [27]. The local injection of human Aβ1-42 into the dentate gyrus increased intracellular Zn2+ in the dentate granule cell layer as reported previously [27–30], while that of human Aβ1-40 and rat Aβ1-42 did not increase intracellular Zn2+ (Fig. 1). However, the local injection of human Aβ1-40 and rat Aβ1-42 attenuated LTP, as well as human Aβ1-42 (Fig. 2).
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Full Length ArticleDifference in ability for extracellular Zn2+ influx between human and rat amyloid β1-42 and its significance

Highlights

Abstract

Introduction

Section snippets

Animals and chemicals

Results

Discussion

Conflicts of interest

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Exp. Neurol.

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Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils

Nat. Struct. Mol. Biol.

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