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Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide

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dc.contributor.author Molina Fernández, Rubén
dc.contributor.author Picón-Pagès, Pol
dc.contributor.author Barranco Almohalla, Alejandro
dc.contributor.author Crepin, Giulia
dc.contributor.author Herrera-Fernández, Víctor
dc.contributor.author García-Elías, Anna
dc.contributor.author Fanlo-Ucar, Hugo
dc.contributor.author Fernàndez Busquets, Xavier
dc.contributor.author García Ojalvo, Jordi
dc.contributor.author Oliva Miguel, Baldomero
dc.contributor.author Muñoz López, Francisco José, 1964-
dc.date.accessioned 2022-11-10T06:50:21Z
dc.date.available 2022-11-10T06:50:21Z
dc.date.issued 2022
dc.identifier.citation Molina-Fernández R, Picón-Pagès P, Barranco-Almohalla A, Crepin G, Herrera-Fernández V, García-Elías A, Fanlo-Ucar H, Fernàndez-Busquets X, García-Ojalvo J, Oliva B, Muñoz FJ. Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide. Brain Commun. 2022 Sep 24;4(5):fcac243. DOI: 10.1093/braincomms/fcac243
dc.identifier.issn 2632-1297
dc.identifier.uri http://hdl.handle.net/10230/54779
dc.description.abstract Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid β-peptide aggregation into β-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid β-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid β-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid β-peptide 1-40. Our results confirm that monomeric amyloid β-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylations and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid β-peptide 1-40 to insulin receptor. We found that oligomeric amyloid β-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid β-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid β-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.
dc.description.sponsorship This work was supported by the Spanish Ministry of Science and Innovation and Agencia Estatal de Investigación plus European Regional Development Fund (FEDER Funds) through grants PID2020-117691RB-I00/AEI/10.13039/501100011033 (F.J.M.), SAF2017-83372-R (F.J.M.), BIO2017-85329-R (B.O.), PGC2018-101251-B-I00 (J.G.-O.) and RTI2018-094579-B-I00 (X.F.-B.). This work was also funded by the Spanish Institute of Health Carlos III by project reference AC20/00009 -FEDER/UE and European Research Era Net (ERANET) ERA-CVD_JTC2020-015 (J.G.-O.), by the ‘María de Maeztu Programme’ for Units of Excellence in Research and Development (R&D; award CEX2018-000792-M), Generalitat de Catalunya (Spain) through the grant 2017-SGR-908 (X.F.-B.) and Fundación QUAES through Cátedra QUAES-UPF de Biomedicina e Ingeniería Biomédica. The Instituto de Salud Global de Barcelona (ISGlobal) and Institute for Bioengineering of Catalonia (IBEC) are members of the Centres de Recerca de Catalunya (CERCA) Programme, Generalitat de Catalunya (Spain). We acknowledge support from the Spanish Ministry of Science, Innovation and Universities through the ‘Centro de Excelencia Severo Ochoa 2019–2023’ Programme (CEX2018-000806-S). This research is part of ISGlobal's Programme on the Molecular Mechanisms of Malaria, which is partially supported by the Fundación Ramón Areces. J.G.-O. also acknowledges support from the Institució Catalana de Recerca i Estudis Avançats (ICREA) Academia programme.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Oxford University Press
dc.relation.ispartof Brain Commun. 2022 Sep 24;4(5):fcac243
dc.rights © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Differential regulation of insulin signalling by monomeric and oligomeric amyloid beta-peptide
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1093/braincomms/fcac243
dc.subject.keyword Akt
dc.subject.keyword Alzheimer’s disease
dc.subject.keyword Amyloid β-peptide
dc.subject.keyword Insulin
dc.subject.keyword Insulin resistance
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/2PE/BIO2017-85329-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-101251-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-094579-B-I00
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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