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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Authors: Corraliza-Gomez, Miriam, Bermejo, Teresa, Lilue, Jingtao, Rodríguez-Iglesias, Noelia, Valero, Jorge, Cozar-Castellano, Irene, Arranz, Eduardo, Sánchez, Diego, Ganfornina, Maria Dolores
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Salamanca (USAL)
Repository:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/154979
Online Access:http://hdl.handle.net/10366/154979
Access Level:Open access
Keyword:Amyloid-beta endocytosis
Cytokine secretion
Inflammation
Insulin-degrading enzyme
Microglia
Microglial proliferation
Myelin phagocytosis
Oxidative stress
Cytokines
Endocytosis
Alzheimer Disease
Phagocytosis
Oxidative Stress
32 Ciencias Médicas
6310.03 Enfermedad
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oai_identifier_str oai:gredos.usal.es:10366/154979
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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-Gomez, MiriamBermejo, TeresaLilue, JingtaoRodríguez-Iglesias, NoeliaValero, JorgeCozar-Castellano, IreneArranz, EduardoSánchez, DiegoGanfornina, Maria DoloresAmyloid-beta endocytosisCytokine secretionInflammationInsulin-degrading enzymeMicrogliaMicroglial proliferationMyelin phagocytosisOxidative stressInflammationCytokinesEndocytosisAlzheimer DiseasePhagocytosisOxidative Stress32 Ciencias Médicas6310.03 EnfermedadThe 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."Margarita Salas postdoctoral grant for the training of young doctors"/Ministerio de Universidades Predoctoral fellowship/Universidad de Valladolid PID2019-110496RB-C21/Ministerio de Ciencia e Innovación PID2019-110911RB-I00/AEI/Ministerio de Ciencia e Innovación VA086G18/Consejería de Educación, Junta de Castilla y León202420242023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10366/154979reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)Inglésinfo:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1549792026-06-07T06:28:51Z
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-Gomez, Miriam
Amyloid-beta endocytosis
Cytokine secretion
Inflammation
Insulin-degrading enzyme
Microglia
Microglial proliferation
Myelin phagocytosis
Oxidative stress
Inflammation
Cytokines
Endocytosis
Alzheimer Disease
Phagocytosis
Oxidative Stress
32 Ciencias Médicas
6310.03 Enfermedad
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-Gomez, Miriam
Bermejo, Teresa
Lilue, Jingtao
Rodríguez-Iglesias, Noelia
Valero, Jorge
Cozar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, Maria Dolores
author Corraliza-Gomez, Miriam
author_facet Corraliza-Gomez, Miriam
Bermejo, Teresa
Lilue, Jingtao
Rodríguez-Iglesias, Noelia
Valero, Jorge
Cozar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, Maria Dolores
author_role author
author2 Bermejo, Teresa
Lilue, Jingtao
Rodríguez-Iglesias, Noelia
Valero, Jorge
Cozar-Castellano, Irene
Arranz, Eduardo
Sánchez, Diego
Ganfornina, Maria Dolores
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Amyloid-beta endocytosis
Cytokine secretion
Inflammation
Insulin-degrading enzyme
Microglia
Microglial proliferation
Myelin phagocytosis
Oxidative stress
Inflammation
Cytokines
Endocytosis
Alzheimer Disease
Phagocytosis
Oxidative Stress
32 Ciencias Médicas
6310.03 Enfermedad
topic Amyloid-beta endocytosis
Cytokine secretion
Inflammation
Insulin-degrading enzyme
Microglia
Microglial proliferation
Myelin phagocytosis
Oxidative stress
Inflammation
Cytokines
Endocytosis
Alzheimer Disease
Phagocytosis
Oxidative Stress
32 Ciencias Médicas
6310.03 Enfermedad
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
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/154979
url http://hdl.handle.net/10366/154979
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411641461833728
score 15,301603

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