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Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation
Alzheimer’s disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740806/ https://www.ncbi.nlm.nih.gov/pubmed/36499491 http://dx.doi.org/10.3390/ijms232315169 |
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author | Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé-Bosch, Sira Galera-López, Lorena Gutiérrez, Daniela A. Ozaita, Andrés Álvarez, Alejandra R. Oliva, Baldomero Muñoz, Francisco J. |
author_facet | Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé-Bosch, Sira Galera-López, Lorena Gutiérrez, Daniela A. Ozaita, Andrés Álvarez, Alejandra R. Oliva, Baldomero Muñoz, Francisco J. |
author_sort | Picón-Pagès, Pol |
collection | PubMed |
description | Alzheimer’s disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aβ oligomers (oAβ) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAβ on CaMKIIα. We found that oAβ produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAβ. |
format | Online Article Text |
id | pubmed-9740806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-97408062022-12-11 Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé-Bosch, Sira Galera-López, Lorena Gutiérrez, Daniela A. Ozaita, Andrés Álvarez, Alejandra R. Oliva, Baldomero Muñoz, Francisco J. Int J Mol Sci Article Alzheimer’s disease (AD) is characterised by the presence of extracellular amyloid plaques in the brain. They are composed of aggregated amyloid beta-peptide (Aβ) misfolded into beta-sheets which are the cause of the AD memory impairment and dementia. Memory depends on the hippocampal formation and maintenance of synapses by long-term potentiation (LTP), whose main steps are the activation of NMDA receptors, the phosphorylation of CaMKIIα and the nuclear translocation of the transcription factor CREB. It is known that Aβ oligomers (oAβ) induce synaptic loss and impair the formation of new synapses. Here, we have studied the effects of oAβ on CaMKIIα. We found that oAβ produce reactive oxygen species (ROS), that induce CaMKIIα oxidation in human neuroblastoma cells as we assayed by western blot and immunofluorescence. Moreover, this oxidized isoform is significantly present in brain samples from AD patients. We found that the oxidized CaMKIIα is active independently of the binding to calcium/calmodulin, and that CaMKIIα phosphorylation is mutually exclusive with CaMKIIα oxidation as revealed by immunoprecipitation and western blot. An in silico modelling of the enzyme was also performed to demonstrate that oxidation induces an activated state of CaMKIIα. In brains from AD transgenic models of mice and in primary cultures of murine hippocampal neurons, we demonstrated that the oxidation of CaMKIIα induces the phosphorylation of CREB and its translocation to the nucleus to promote the transcription of ARC and BDNF. Our data suggests that CaMKIIα oxidation would be a pro-survival mechanism that is triggered when a noxious stimulus challenges neurons as do oAβ. MDPI 2022-12-02 /pmc/articles/PMC9740806/ /pubmed/36499491 http://dx.doi.org/10.3390/ijms232315169 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé-Bosch, Sira Galera-López, Lorena Gutiérrez, Daniela A. Ozaita, Andrés Álvarez, Alejandra R. Oliva, Baldomero Muñoz, Francisco J. Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title | Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title_full | Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title_fullStr | Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title_full_unstemmed | Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title_short | Amyloid β-Peptide Causes the Permanent Activation of CaMKIIα through Its Oxidation |
title_sort | amyloid β-peptide causes the permanent activation of camkiiα through its oxidation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740806/ https://www.ncbi.nlm.nih.gov/pubmed/36499491 http://dx.doi.org/10.3390/ijms232315169 |
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