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ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells
Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca(2+) imbalances in the pathophysiology of both spora...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432374/ https://www.ncbi.nlm.nih.gov/pubmed/32722509 http://dx.doi.org/10.3390/ijms21155288 |
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author | Scremin, Elena Agostini, Mario Leparulo, Alessandro Pozzan, Tullio Greotti, Elisa Fasolato, Cristina |
author_facet | Scremin, Elena Agostini, Mario Leparulo, Alessandro Pozzan, Tullio Greotti, Elisa Fasolato, Cristina |
author_sort | Scremin, Elena |
collection | PubMed |
description | Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca(2+) imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca(2+) entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in Aβ accumulation in different model cells. In neurons, both the role and components of SOCE remain quite obscure, whereas in astrocytes, SOCE controls their Ca(2+)-based excitability and communication to neurons. Glial cells are also directly involved in Aβ production and clearance. Here, we focus on the role of ORAI2, a key SOCE component, in modulating SOCE in the human neuroglioma cell line H4. We show that ORAI2 overexpression reduces both SOCE level and stores Ca(2+) content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca(2+) handling. In Aβ-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases Aβ42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation. |
format | Online Article Text |
id | pubmed-7432374 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74323742020-08-24 ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells Scremin, Elena Agostini, Mario Leparulo, Alessandro Pozzan, Tullio Greotti, Elisa Fasolato, Cristina Int J Mol Sci Article Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca(2+) imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca(2+) entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in Aβ accumulation in different model cells. In neurons, both the role and components of SOCE remain quite obscure, whereas in astrocytes, SOCE controls their Ca(2+)-based excitability and communication to neurons. Glial cells are also directly involved in Aβ production and clearance. Here, we focus on the role of ORAI2, a key SOCE component, in modulating SOCE in the human neuroglioma cell line H4. We show that ORAI2 overexpression reduces both SOCE level and stores Ca(2+) content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca(2+) handling. In Aβ-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases Aβ42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation. MDPI 2020-07-25 /pmc/articles/PMC7432374/ /pubmed/32722509 http://dx.doi.org/10.3390/ijms21155288 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Scremin, Elena Agostini, Mario Leparulo, Alessandro Pozzan, Tullio Greotti, Elisa Fasolato, Cristina ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title | ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title_full | ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title_fullStr | ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title_full_unstemmed | ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title_short | ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells |
title_sort | orai2 down-regulation potentiates soce and decreases aβ42 accumulation in human neuroglioma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432374/ https://www.ncbi.nlm.nih.gov/pubmed/32722509 http://dx.doi.org/10.3390/ijms21155288 |
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