Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>

Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulat...

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Autores principales:	Veronica D’Ezio, Marco Colasanti, Tiziana Persichini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Aβ<sub>25-35</sub> Alzheimer’s disease amyloid-β astrocytes Nrf2 oxidative stress Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/1dc1c18c82e54289a339152b5689121f
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spelling	oai:doaj.org-article:1dc1c18c82e54289a339152b5689121f2021-11-25T16:26:05ZAmyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>10.3390/antiox101116852076-3921https://doaj.org/article/1dc1c18c82e54289a339152b5689121f2021-10-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1685https://doaj.org/toc/2076-3921Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of several phase II detoxifying and antioxidant genes, such as the System X<sub>c</sub><sup>−</sup> subunit xCT. Here, we studied (i) the effect of the Aβ fragment 25-35 (Aβ<sub>25-35</sub>) on Nrf2-dependent System X<sub>c</sub><sup>−</sup> expression in U373 human astroglial cells and (ii) the effect of Aβ<sub>25-35</sub>-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aβ<sub>25-35</sub> was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System X<sub>c</sub><sup>−</sup> up-regulation. However, this astrocytic response caused an enhanced cell mortality of co-cultured SH-SY5Y cells, taken as a neuronal model. Consistently, the specific System X<sub>c</sub><sup>−</sup> inhibitor sulfasalazine prevented the increase of both neuronal mortality and extracellular glutamate levels, thus indicating that the neurotoxic effect was due to an augmented release of glutamate through the transporter. The involvement of NMDA receptor activation in this pathway was also demonstrated using the specific inhibitor MK801 that completely restored neuronal viability at the control levels. The present study sheds light on the Nrf2/system X<sub>c</sub><sup>−</sup> pathway in the toxicity induced by Aβ<sub>25-35</sub> and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer’s disease.Veronica D’EzioMarco ColasantiTiziana PersichiniMDPI AGarticleAβ<sub>25-35</sub>Alzheimer’s diseaseamyloid-βastrocytesNrf2oxidative stressTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1685, p 1685 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aβ<sub>25-35</sub> Alzheimer’s disease amyloid-β astrocytes Nrf2 oxidative stress Therapeutics. Pharmacology RM1-950
spellingShingle	Aβ<sub>25-35</sub> Alzheimer’s disease amyloid-β astrocytes Nrf2 oxidative stress Therapeutics. Pharmacology RM1-950 Veronica D’Ezio Marco Colasanti Tiziana Persichini Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
description	Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of several phase II detoxifying and antioxidant genes, such as the System X<sub>c</sub><sup>−</sup> subunit xCT. Here, we studied (i) the effect of the Aβ fragment 25-35 (Aβ<sub>25-35</sub>) on Nrf2-dependent System X<sub>c</sub><sup>−</sup> expression in U373 human astroglial cells and (ii) the effect of Aβ<sub>25-35</sub>-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aβ<sub>25-35</sub> was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System X<sub>c</sub><sup>−</sup> up-regulation. However, this astrocytic response caused an enhanced cell mortality of co-cultured SH-SY5Y cells, taken as a neuronal model. Consistently, the specific System X<sub>c</sub><sup>−</sup> inhibitor sulfasalazine prevented the increase of both neuronal mortality and extracellular glutamate levels, thus indicating that the neurotoxic effect was due to an augmented release of glutamate through the transporter. The involvement of NMDA receptor activation in this pathway was also demonstrated using the specific inhibitor MK801 that completely restored neuronal viability at the control levels. The present study sheds light on the Nrf2/system X<sub>c</sub><sup>−</sup> pathway in the toxicity induced by Aβ<sub>25-35</sub> and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer’s disease.
format	article
author	Veronica D’Ezio Marco Colasanti Tiziana Persichini
author_facet	Veronica D’Ezio Marco Colasanti Tiziana Persichini
author_sort	Veronica D’Ezio
title	Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
title_short	Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
title_full	Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
title_fullStr	Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
title_full_unstemmed	Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>
title_sort	amyloid-β 25-35 induces neurotoxicity through the up-regulation of astrocytic system x<sub>c</sub><sup>−</sup>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1dc1c18c82e54289a339152b5689121f
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Amyloid-β 25-35 Induces Neurotoxicity through the Up-Regulation of Astrocytic System X<sub>c</sub><sup>−</sup>

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