Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging

The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme...

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Autores: Corraliza-Gómez, Miriam, Bermejo, Teresa, Lilue, Jingtao, Rodriguez-Iglesias, Noelia, Valero, Jorge, Cózar-Castellano, Irene, Arranz, Eduardo, Sánchez, Diego, Ganfornina, M. D.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/342538
Acceso en línea:http://hdl.handle.net/10261/342538
Access Level:acceso abierto
Palabra clave:Insulin-degrading enzyme
Microglia
Myelin phagocytosis
Amyloid-beta endocytosis
Inflammation
Oxidative stress
Microglial proliferation
Cytokine secretion
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spelling Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain agingCorraliza-Gómez, MiriamBermejo, TeresaLilue, JingtaoRodriguez-Iglesias, NoeliaValero, JorgeCózar-Castellano, IreneArranz, EduardoSánchez, DiegoGanfornina, M. D.Insulin-degrading enzymeMicrogliaMyelin phagocytosisAmyloid-beta endocytosisInflammationOxidative stressMicroglial proliferationCytokine secretionThe insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.This research was funded by a Ministerio de Ciencia e Innovacion grant PID2019-110911RB-I00/AEI/10.13039/501100011033 to M.D.G. and D.S.; grant PID2019-110496RB-C21 to I.C.; Consejería de Educación Junta Castilla y León grant VA086G18 to MDG; University of Valladolid predoctoral fellowship (#call 2016) to M.C.-G. and “Margarita Salas postdoctoral grant for the training of young doctors” funded by NextGenerationEU and Spanish Ministry of Universities” (#call 2022, University of Valladolid) to M.C.-G.Peer reviewedBioMed CentralMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Junta de Castilla y LeónUniversidad de ValladolidMinisterio de Universidades (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420232024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/342538reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110911RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C21The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI http://dx.doi.org/10.1186/s12974-023-02914-7http://dx.doi.org/10.1186/s12974-023-02914-7Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3425382026-05-22T06:33:51Z
dc.title.none.fl_str_mv Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
title Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
spellingShingle Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
Corraliza-Gómez, Miriam
Insulin-degrading enzyme
Microglia
Myelin phagocytosis
Amyloid-beta endocytosis
Inflammation
Oxidative stress
Microglial proliferation
Cytokine secretion
title_short Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
title_full Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
title_fullStr Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
title_full_unstemmed Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
title_sort Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer’s disease and brain aging
dc.creator.none.fl_str_mv Corraliza-Gómez, Miriam
Bermejo, Teresa
Lilue, Jingtao
Rodriguez-Iglesias, Noelia
Valero, Jorge
Cózar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, M. D.
author Corraliza-Gómez, Miriam
author_facet Corraliza-Gómez, Miriam
Bermejo, Teresa
Lilue, Jingtao
Rodriguez-Iglesias, Noelia
Valero, Jorge
Cózar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, M. D.
author_role author
author2 Bermejo, Teresa
Lilue, Jingtao
Rodriguez-Iglesias, Noelia
Valero, Jorge
Cózar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, M. D.
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Junta de Castilla y León
Universidad de Valladolid
Ministerio de Universidades (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Insulin-degrading enzyme
Microglia
Myelin phagocytosis
Amyloid-beta endocytosis
Inflammation
Oxidative stress
Microglial proliferation
Cytokine secretion
topic Insulin-degrading enzyme
Microglia
Myelin phagocytosis
Amyloid-beta endocytosis
Inflammation
Oxidative stress
Microglial proliferation
Cytokine secretion
description The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/342538
url http://hdl.handle.net/10261/342538
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110911RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C21
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI http://dx.doi.org/10.1186/s12974-023-02914-7
http://dx.doi.org/10.1186/s12974-023-02914-7
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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