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 forma...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universitat Pompeu Fabra |
| Repositorio: | Repositorio Digital de la UPF |
| OAI Identifier: | oai:repositori.upf.edu:10230/55312 |
| Acceso en línea: | http://hdl.handle.net/10230/55312 http://dx.doi.org/10.3390/ijms232315169 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer’s disease CREB CaMKIIα Amyloid Oxidative stress |
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Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidationPicón-Pagès, PolFanlo-Ucar, HugoHerrera-Fernández, VíctorAusellé Bosch, SiraGalera López, Lorena, 1993-Gutiérrez, Daniela A.Ozaita Mintegui, Andrés, 1969-Álvarez, Alejandra R.Oliva Miguel, BaldomeroMuñoz López, Francisco José, 1964-Alzheimer’s diseaseCREBCaMKIIαAmyloidOxidative stressAlzheimer'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.This work was supported by the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación plus FEDER Funds through grants PID2020-117691RB-I00/AEI/10.13039/501100011033 (F.J.M.), SAF2017-83372-R (F.J.M.), BIO 2020-113203RB (B.O.) and PID2021-123482OB-I00 (A.O.). This work was also funded by the “María de Maetzu Programme” for Units of Excellence in R&D and the MM-MELIS intercollaborative projects (award CEX2018-000792-M/IPEP-MM2020-5). Funding for this project was also from the Comisión Nacional de Investigación Científica y Tecnológica-Chile: Fondecyt 12011668 (to A.R.Á.) and Millennium Science Initiative Program—ICN09_016/ICN 2021_045 (to A.R.Á.).MDPI202320232022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/55312http://dx.doi.org/10.3390/ijms232315169reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésInt J Mol Sci. 2022 Dec 2;23(23):15169info:eu-repo/grantAgreement/ES/2PE/PID2020-117691RB-I00info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-Rinfo:eu-repo/grantAgreement/ES/1PE/BIO2020-113203RBinfo:eu-repo/grantAgreement/ES/2PE/PID2021-123482OB-I00© 2022 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 (https://creativecommons.org/licenses/by/4.0/).https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/553122026-06-12T07:21:37Z |
| dc.title.none.fl_str_mv |
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 |
| spellingShingle |
Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation Picón-Pagès, Pol Alzheimer’s disease CREB CaMKIIα Amyloid Oxidative stress |
| title_short |
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_sort |
Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation |
| dc.creator.none.fl_str_mv |
Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé Bosch, Sira Galera López, Lorena, 1993- Gutiérrez, Daniela A. Ozaita Mintegui, Andrés, 1969- Álvarez, Alejandra R. Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author |
Picón-Pagès, Pol |
| author_facet |
Picón-Pagès, Pol Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé Bosch, Sira Galera López, Lorena, 1993- Gutiérrez, Daniela A. Ozaita Mintegui, Andrés, 1969- Álvarez, Alejandra R. Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author_role |
author |
| author2 |
Fanlo-Ucar, Hugo Herrera-Fernández, Víctor Ausellé Bosch, Sira Galera López, Lorena, 1993- Gutiérrez, Daniela A. Ozaita Mintegui, Andrés, 1969- Álvarez, Alejandra R. Oliva Miguel, Baldomero Muñoz López, Francisco José, 1964- |
| author2_role |
author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Alzheimer’s disease CREB CaMKIIα Amyloid Oxidative stress |
| topic |
Alzheimer’s disease CREB CaMKIIα Amyloid Oxidative stress |
| 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. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2023 2023 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10230/55312 http://dx.doi.org/10.3390/ijms232315169 |
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http://hdl.handle.net/10230/55312 http://dx.doi.org/10.3390/ijms232315169 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
| dc.relation.none.fl_str_mv |
Int J Mol Sci. 2022 Dec 2;23(23):15169 info:eu-repo/grantAgreement/ES/2PE/PID2020-117691RB-I00 info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-R info:eu-repo/grantAgreement/ES/1PE/BIO2020-113203RB info:eu-repo/grantAgreement/ES/2PE/PID2021-123482OB-I00 |
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https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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