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Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner

As in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in...

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Autores principales: Tsutsui, Shigeki, Morgan, Megan, Tedford, Hugo, You, Haitao, Zamponi, Gerald W., Stys, Peter K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327403/
https://www.ncbi.nlm.nih.gov/pubmed/35883145
http://dx.doi.org/10.1186/s13041-022-00955-2
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author Tsutsui, Shigeki
Morgan, Megan
Tedford, Hugo
You, Haitao
Zamponi, Gerald W.
Stys, Peter K.
author_facet Tsutsui, Shigeki
Morgan, Megan
Tedford, Hugo
You, Haitao
Zamponi, Gerald W.
Stys, Peter K.
author_sort Tsutsui, Shigeki
collection PubMed
description As in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in an NMDAR-dependent manner. Chelating Cu in the perfusate induced a substantial increase in Ca levels, and also caused significant axo-myelinic injury. Myelinic NMDARs are shown to be regulated by cellular prion protein; only in prion protein KO optic nerves does application of NMDA + D-serine induce a large Ca increase, consistent with strong desensitization of these receptors in the presence of prion protein limiting Ca overload. Aβ(1-42) peptide induced a large Ca increase that was also Cu-dependent, and was blocked by NMDAR antagonism. Our results indicate that like in neurons, myelinic NMDARs permeate potentially injurious amounts of Ca, and are also potently regulated by micromolar Cu and activated by Aβ(1-42) peptides. These findings shed mechanistic light on the important primary white matter injury frequently observed in Alzheimer's brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00955-2.
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spelling pubmed-93274032022-07-28 Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner Tsutsui, Shigeki Morgan, Megan Tedford, Hugo You, Haitao Zamponi, Gerald W. Stys, Peter K. Mol Brain Micro Report As in neurons, CNS myelin expresses N-Methyl-D-Aspartate Receptors (NMDARs) that subserve physiological roles, but have the potential to induce injury to this vital element. Using 2-photon imaging of myelinic Ca in live ex vivo mouse optic nerves, we show that Cu ions potently modulate Ca levels in an NMDAR-dependent manner. Chelating Cu in the perfusate induced a substantial increase in Ca levels, and also caused significant axo-myelinic injury. Myelinic NMDARs are shown to be regulated by cellular prion protein; only in prion protein KO optic nerves does application of NMDA + D-serine induce a large Ca increase, consistent with strong desensitization of these receptors in the presence of prion protein limiting Ca overload. Aβ(1-42) peptide induced a large Ca increase that was also Cu-dependent, and was blocked by NMDAR antagonism. Our results indicate that like in neurons, myelinic NMDARs permeate potentially injurious amounts of Ca, and are also potently regulated by micromolar Cu and activated by Aβ(1-42) peptides. These findings shed mechanistic light on the important primary white matter injury frequently observed in Alzheimer's brain. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13041-022-00955-2. BioMed Central 2022-07-26 /pmc/articles/PMC9327403/ /pubmed/35883145 http://dx.doi.org/10.1186/s13041-022-00955-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Micro Report
Tsutsui, Shigeki
Morgan, Megan
Tedford, Hugo
You, Haitao
Zamponi, Gerald W.
Stys, Peter K.
Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title_full Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title_fullStr Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title_full_unstemmed Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title_short Copper ions, prion protein and Aβ modulate Ca levels in central nervous system myelin in an NMDA receptor-dependent manner
title_sort copper ions, prion protein and aβ modulate ca levels in central nervous system myelin in an nmda receptor-dependent manner
topic Micro Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9327403/
https://www.ncbi.nlm.nih.gov/pubmed/35883145
http://dx.doi.org/10.1186/s13041-022-00955-2
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