Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation

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• dc.contributor.author Picón-Pagès, Pol
• dc.contributor.author Fanlo-Ucar, Hugo
• dc.contributor.author Herrera-Fernández, Víctor
• dc.contributor.author Ausellé Bosch, Sira
• dc.contributor.author Galera López, Lorena, 1993-
• dc.contributor.author Gutiérrez, Daniela A.
• dc.contributor.author Ozaita Mintegui, Andrés, 1969-
• dc.contributor.author Álvarez, Alejandra R.
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Muñoz López, Francisco José, 1964-
• dc.date.accessioned 2023-01-17T12:57:23Z
• dc.date.available 2023-01-17T12:57:23Z
• dc.date.issued 2022
• dc.description.abstract 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.
• dc.description.sponsorship 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.).
• dc.format.mimetype application/pdf
• dc.identifier.citation Picón-Pagès P, Fanlo-Ucar H, Herrera-Fernández V, Ausellé-Bosch S, Galera-López L, Gutiérrez DA, Ozaita A, Álvarez AR, Oliva B, Muñoz FJ. Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation. Int J Mol Sci. 2022 Dec 2;23(23):15169. DOI: 10.3390/ijms232315169
• dc.identifier.doi http://dx.doi.org/10.3390/ijms232315169
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/55312
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2022 Dec 2;23(23):15169
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117691RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-83372-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2020-113203RB
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2021-123482OB-I00
• dc.rights © 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/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Alzheimer’s disease
• dc.subject.keyword CREB
• dc.subject.keyword CaMKIIα
• dc.subject.keyword Amyloid
• dc.subject.keyword Oxidative stress
• dc.title Amyloid β-peptide causes the permanent activation of CaMKIIα through its oxidation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion