Extracellular Zn2+-independently attenuated LTP by human amyloid β1-40 and rat amyloid β1-42

doi:10.1016/j.bbrc.2019.05.037

Biochemical and Biophysical Research Communications

Volume 514, Issue 3, 30 June 2019, Pages 888-892

https://doi.org/10.1016/j.bbrc.2019.05.037 Get rights and content

Highlights

•
LTP was attenuated after injection of human Aβ_1-40 and rat Aβ_1-42 into the dentate gyrus.
•
Human Aβ_1-40 and rat Aβ_1-42 did not increase intracellular Zn²⁺ in the dentate gyrus.
•
Human Aβ_1-40 and rat Aβ_1-42 attenuated in the presence of CaEDTA.
•
Human Aβ_1-40 and rat Aβ_1-42 affect LTP via extracellular Zn²⁺-independent mechanism at low micromolar concentration.

Abstract

Human amyloid-β_1-40 (Aβ_1-40) and rat Aβ_1-42 have lower affinity for extracellular Zn²⁺ than human Aβ_1-42. Here we report extracellular Zn²⁺-independent attenuation of dentate gyrus long-term potentiation (LTP) by human Aβ_1-40 and rat Aβ_1-42. On the basis of the data that dentate gyrus LTP is extracellular Zn²⁺-dependently attenuated after local injection of human Aβ_1-42 (25 pmol, 1 μl) into the dentate gyrus, which increases intracellular Zn²⁺ in the dentate gyrus, the toxicity of human Aβ_1-40 and rat Aβ_1-42 was compared in the in vivo system with human Aβ_1-42. Dentate gyrus LTP was attenuated after injection of human Aβ_1-40 and rat Aβ_1-42 (25 pmol, 1 μl) into the dentate gyrus, which did not increase intracellular Zn²⁺ in the dentate gyrus. The attenuated LTP was not rescued by co-injection of CaEDTA, an extracellular Zn²⁺ chelator. The present study suggests that human Aβ_1-40 and rat Aβ_1-42 affect cognitive activity via extracellular Zn²⁺-independent mechanism at low micromolar concentration.

Introduction

Amyloid-β peptide (Aβ) is physiologically secreted into extracellular space in the brain after a sequential cleavage of amyloid precursor protein (APP) [1,2] and the physiological concentration of Aβ is estimated to be in the picomolar range in rodents [3]. The peptide has a characteristic of self-assembly into oligomers, protofibrils and fibrils [4]. In the human brain, Aβ_1-40 and Aβ_1-42 are mainly produced forms and Aβ_1-40 concentration is approximately 10 times higher than Aβ_1-42 concentration in biological fluids [5]. Because Aβ_1-42 is more readily prone to form oligomers, on the other hand, it is more neurotoxic than Aβ_1-40 [6,7].

Aβ release from synaptic vesicles is thought to be the primary mediator of dynamic changes in endogenous Aβ levels in the brain extracellular compartment, which are independent on changes in APP processing [8]. Aβ levels in the brain extracellular fluid may be involved in cognitive activity via modification of synaptic plasticity such as long-term potentiation (LTP), the cellular mechanism of learning and memory [8].

Aβ peptides have been implicated in the central theory of the hypothesis on Alzheimer disease (AD) pathogenesis, because the peptides are the principal components of the amyloid plaque that is a main pathological hallmark of AD. Endogenous Aβ can induce synapse dysfunction through uncertain mechanisms and contribute to cognitive decline in the pre-dementia stage of AD [9,10]. High levels of human Aβ in the brain extracellular compartment significantly attenuate LTP in mice and rats, followed by memory loss [[11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]].

Because Zn²⁺ readily accelerates Aβ oligomerization, it has been implicated in the AD pathogenesis [24,25]. The trial for drug therapy targeting metal ions, e.g., Zn²⁺ has been reported for AD [26]. We have been reported that human Aβ_1-42, unlike human Aβ_1-40, takes extracellular Zn²⁺ as a cargo into dentate granule cells in the rat brain and readily leads to cognitive decline via attenuated LTP [[27], [28], [29]]. On the basis of the data that the cognitive decline is extracellular Zn²⁺-dependently induced, in the present paper, the toxicity of human Aβ_1-40 and rat Aβ_1-42, which have lower affinity for Zn²⁺ than human Aβ_1-42 [30], was compared in the in vivo system with human Aβ_1-42 (Fig. 1).

Section snippets

Animals and chemicals

Wistar rats (male, 7–9 weeks of age, Japan SLC, Hamamatsu) were caged under the standard conditions with a diurnal 12-h light cycle. The room temperature and relative humidity were controlled at 23 ± 1 °C and 55 ± 5%, respectively. The rats were allowed free access to a standard laboratory food and water. The experiments were done 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

Results

Intracellular Zn²⁺ is rapidly increased in dentate granule cells after local injection of human Aβ_1-42 (25 μM, 1 μl) into the dentate gyrus of young rats [27]. Aβ_1-42 captures extracellular Zn²⁺ in the extracellular compartment and both levels of Aβ_1-42 and Zn²⁺ are rapidly increased in dentate granule cells, followed by cognitive decline via attenuated LTP at the perforant pathway-dentate granule cell synapses. The cognitive decline is due to Aβ_1-42-induced increase in intracellular Zn²⁺ in

Discussion

On the basis of the evidence that extracellular Zn²⁺ plays a key for human Aβ_1-42 toxicity [[27], [28], [29], [30]], here ability of human Aβ_1-42 for the influx of extracellular Zn²⁺ into dentate granule cells of rats was compared with human Aβ_1-40 and rat Aβ_1-42. Intracellular Zn²⁺ is increased in dentate granule cells 5 min after local injection of human Aβ_1-42 (25 μM, 1 μl) into the dentate granule cell layer, which subsequently attenuates LTP [27], but not after local injection of Aβ_1-42

Conflicts of interest

There are no conflicts to declare.

References (38)

L. Gu et al.
A new structural model of Alzheimer's Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling
J. Struct. Biol.
(2016)
D.J. Selkoe
Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior
Behav. Brain Res.
(2008)
J.R. Cirrito et al.
Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo
Neuron
(2005)
K.P. Kepp
Alzheimer's disease due to loss of function: a new synthesis of the available data
Prog. Neurobiol.
(2016)
A. Itoh et al.
Impairments of long-term potentiation in hippocampal slices of beta-amyloid-infused rats
Eur. J. Pharmacol.
(1999)
H. Tamano et al.
Difference in ability for extracellular Zn²⁺ influx between human and rat amyloid β_1-42 and its significance
Neurotoxicology
(2019)
P.J. Nestor et al.
Advances in the early detection of Alzheimer's disease
Nat. Med.
(2004)
H.W. Querfurth et al.
Alzheimer's disease
N. Engl. J. Med.
(2010)
J.R. Cirrito et al.
In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life
J. Neurosci.
(2003)
N.S. Schoonenboom et al.
Amyloid beta 38, 40, and 42 species in cerebrospinal fluid: more of the same?
Ann. Neurol.
(2005)

L. Mucke et al.

High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation

J. Neurosci.

(2000)

R.J. Perrin et al.

Multimodal techniques for diagnosis and prognosis of Alzheimer's disease

Nature

(2009)

W.K. Cullen et al.

Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments

Neuroreport

(1997)

M.P. Lambert et al.

Nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins

Proc. Natl. Acad. Sci. U.S.A.

(1998)

Q.S. Chen et al.

Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides

J. Neurosci. Res.

(2000)

D.B. Freir et al.

Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo

J. Neurophysiol.

(2001)

J.H. Kim et al.

Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo

J. Neurosci.

(2001)

A. Stephan et al.

Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits

J. Neurosci.

(2001)

O.V. Vitolo et al.

Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling

Proc. Natl. Acad. Sci. U.S.A.

(2002)

Cited by (10)

Zinc
2021, Advances in Food and Nutrition Research
Citation Excerpt :
In addition, direct interaction of extracellular Zn2 + with Aβ1–42 was shown to be essential for its uptake into rat hippocampus, whereas the uptake of both species was blocked by Ca2 + -EDTA (Takeda et al., 2017). At the same time, neither human Aβ1–40 nor rat Aβ1–42 injection (25 pmol, 1 μL) did not increase intracellular Zn2 + levels in the dentate gyrus, indicating a Zn-independent mechanism of toxicity (Tamano, Takiguchi, Shimaya, et al., 2019; Tamano, Takiguchi, Tanaka, et al., 2019). The existing contradictions may have resulted from different methodological approaches to assess Zn-Ab interaction, as well as the animal species used in the experiments (Arena & Rizzarelli, 2019).
Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010 − 20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn^2 + and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn^2 + metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid β and α-synuclein processing with subsequent toxic effects. Zn^2 + was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2 + in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn^2 + was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.
Adrenergic β receptor activation reduces amyloid β<inf>1-42</inf>-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP
2020, NeuroToxicology
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.
Botanical Mixture Containing Nitric Oxide Metabolite Enhances Neural Plasticity to Improve Cognitive Impairment in a Vascular Dementia Rat Model
2023, Nutrients
Isoproterenol, an adrenergic β receptor agonist, induces metallothionein synthesis followed by canceling amyloid β<inf>1-42</inf>-induced neurodegeneration
2022, BioMetals
Dehydroeffusol Pprevents Amyloid β<inf>1-42</inf>-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn2+ Toxicity
2021, Molecular Neurobiology
Real-time detection and imaging of exogenous and endogenous Zn2+in the PC12 cell model of depression with a NIR fluorescent probe
2021, Analyst

View all citing articles on Scopus

View full text

Extracellular Zn2+-independently attenuated LTP by human amyloid β1-40 and rat amyloid β1-42

Highlights

Abstract

Introduction

Section snippets

Animals and chemicals

Results

Discussion

Conflicts of interest

J. Struct. Biol.

Behav. Brain Res.

Neuron

Prog. Neurobiol.

Eur. J. Pharmacol.

Neurotoxicology

Advances in the early detection of Alzheimer's disease

Nat. Med.

Alzheimer's disease

N. Engl. J. Med.

In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-β metabolism and half-life

J. Neurosci.

Amyloid beta 38, 40, and 42 species in cerebrospinal fluid: more of the same?

Ann. Neurol.

High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation

J. Neurosci.

Multimodal techniques for diagnosis and prognosis of Alzheimer's disease

Nature

Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments

Neuroreport

Nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins

Proc. Natl. Acad. Sci. U.S.A.

Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides

J. Neurosci. Res.

Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo

J. Neurophysiol.

Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo

J. Neurosci.

Generation of aggregated beta-amyloid in the rat hippocampus impairs synaptic transmission and plasticity and causes memory deficits

J. Neurosci.

Amyloid beta-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling

Proc. Natl. Acad. Sci. U.S.A.

Extracellular Zn²⁺-independently attenuated LTP by human amyloid β_1-40 and rat amyloid β_1-42