Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1
Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2021 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/260192 |
| Acesso em linha: | http://hdl.handle.net/10261/260192 |
| Access Level: | acceso abierto |
| Palavra-chave: | Hypoxia Alzheimer’s disease Microglia HIF1 Aerobic respiration Anaerobic glycolysis |
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oai:digital.csic.es:10261/260192 |
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España |
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| dc.title.none.fl_str_mv |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| title |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| spellingShingle |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 March Díaz, Rosana Hypoxia Alzheimer’s disease Microglia HIF1 Aerobic respiration Anaerobic glycolysis |
| title_short |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| title_full |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| title_fullStr |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| title_full_unstemmed |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| title_sort |
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1 |
| dc.creator.none.fl_str_mv |
March Díaz, Rosana Lara-Ureña, Nieves Romero-Molina, Carmen Heras-Garvin, Antonio Ortega de San Luis, Clara Álvarez-Vergara, María I. Sánchez García, Manuel A. Sánchez-Mejias, Elisabeth Dávila, José C. Rosales-Nieves, Alicia E. Forja, Cristina Navarro-Garrido, Victoria Gómez-Arboledas, Ángela Sánchez-Mico, María V. Viehweger, Adrian Gerpe, Almudena Hodson, Emma J. Vizuete, Marisa Bishop, Tammie Serrano-Pozo, Alberto López-Barneo, José Berra, Edurne Vitorica, Javier Pascual Bravo, Alberto |
| author |
March Díaz, Rosana |
| author_facet |
March Díaz, Rosana Lara-Ureña, Nieves Romero-Molina, Carmen Heras-Garvin, Antonio Ortega de San Luis, Clara Álvarez-Vergara, María I. Sánchez García, Manuel A. Sánchez-Mejias, Elisabeth Dávila, José C. Rosales-Nieves, Alicia E. Forja, Cristina Navarro-Garrido, Victoria Gómez-Arboledas, Ángela Sánchez-Mico, María V. Viehweger, Adrian Gerpe, Almudena Hodson, Emma J. Vizuete, Marisa Bishop, Tammie Serrano-Pozo, Alberto López-Barneo, José Berra, Edurne Vitorica, Javier Pascual Bravo, Alberto |
| author_role |
author |
| author2 |
Lara-Ureña, Nieves Romero-Molina, Carmen Heras-Garvin, Antonio Ortega de San Luis, Clara Álvarez-Vergara, María I. Sánchez García, Manuel A. Sánchez-Mejias, Elisabeth Dávila, José C. Rosales-Nieves, Alicia E. Forja, Cristina Navarro-Garrido, Victoria Gómez-Arboledas, Ángela Sánchez-Mico, María V. Viehweger, Adrian Gerpe, Almudena Hodson, Emma J. Vizuete, Marisa Bishop, Tammie Serrano-Pozo, Alberto López-Barneo, José Berra, Edurne Vitorica, Javier Pascual Bravo, Alberto |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Instituto de Salud Carlos III Ministerio de Educación, Cultura y Deporte (España) Ministerio de Economía, Industria y Competitividad (España) European Commission Junta de Andalucía Fundación Domingo Martínez Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Hypoxia Alzheimer’s disease Microglia HIF1 Aerobic respiration Anaerobic glycolysis |
| topic |
Hypoxia Alzheimer’s disease Microglia HIF1 Aerobic respiration Anaerobic glycolysis |
| description |
Genetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2022 2022 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_816b Postprint info:eu-repo/semantics/acceptedVersion |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/preprint |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/260192 |
| url |
http://hdl.handle.net/10261/260192 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
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Springer Nature |
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Springer Nature |
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reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
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Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1March Díaz, RosanaLara-Ureña, NievesRomero-Molina, CarmenHeras-Garvin, AntonioOrtega de San Luis, ClaraÁlvarez-Vergara, María I.Sánchez García, Manuel A.Sánchez-Mejias, ElisabethDávila, José C.Rosales-Nieves, Alicia E.Forja, CristinaNavarro-Garrido, VictoriaGómez-Arboledas, ÁngelaSánchez-Mico, María V.Viehweger, AdrianGerpe, AlmudenaHodson, Emma J.Vizuete, MarisaBishop, TammieSerrano-Pozo, AlbertoLópez-Barneo, JoséBerra, EdurneVitorica, JavierPascual Bravo, AlbertoHypoxiaAlzheimer’s diseaseMicrogliaHIF1Aerobic respirationAnaerobic glycolysisGenetic Alzheimer’s disease (AD) risk factors associate with reduced defensive amyloid β plaque-associated microglia (AβAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AβAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aβ plaque microglial coverage and an increase of Aβ plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.R.M.-D. was the recipient of a Sara Borrell fellowship from Instituto de Salud Carlos III (ISCIII) (CD09/0007). N.L.-U., C.O.-d.S.L., C.R.-M. and M.I.A.-V. were the recipients of FPU fellowships from Spanish Ministry of Education, Culture and Sport (FPU14/02115, AP2010‐1598, FPU16/02050 and FPU15/02898, respectively). A.H.-G. was the recipient of an FPI fellowship from the Spanish Ministry of Education, Culture and Sport (BES-2010-033886). This work was supported by grants from the Spanish MINEICO, ISCIII and FEDER (European Union) (SAF2012‐33816, SAF2015‐64111‐R, SAF2017-90794-REDT and PIE13/0004 to A.P.); by the Regional Government of Andalusia co-funded by CEC and FEDER funds (European Union) (‘Proyectos de Excelencia’; P12‐CTS‐2138 and P12‐CTS‐2232 to A.P.); by the ‘Ayuda de Biomedicina 2018’, Fundación Domingo Martínez (to A.P.) ; by the ISCIII of Spain, co-financed by FEDER funds (European Union) through grants PI18/01556 (to J.V.) and PI18/01557 (to A. Gutierrez); by Junta de Andalucía, co-financed by FEDER funds (grants UMA18-FEDERJA-211 (to A. Gutierrez) and US‐1262734 (to J.V.)); and by Spanish MINEICO (BFU2016-76872-R and BES-2011-047721 to E.B.).Peer reviewedSpringer NatureInstituto de Salud Carlos IIIMinisterio de Educación, Cultura y Deporte (España)Ministerio de Economía, Industria y Competitividad (España)European CommissionJunta de AndalucíaFundación Domingo MartínezConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_816bPostprintinfo:eu-repo/semantics/acceptedVersioninfo:eu-repo/semantics/preprintapplication/pdfhttp://hdl.handle.net/10261/260192reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MECD//FPU14%2F02115info:eu-repo/grantAgreement/MECD//AP2010‐1598info:eu-repo/grantAgreement/MECD//FPU16%2F02050info:eu-repo/grantAgreement/MECD//FPU15%2F02898info:eu-repo/grantAgreement/MINECO//SAF2012‐33816info:eu-repo/grantAgreement/MINECO//SAF2015‐64111‐Rinfo:eu-repo/grantAgreement/MINECO//SAF2017-90794-REDTinfo:eu-repo/grantAgreement/MINECO//BFU2016-76872-Rinfo:eu-repo/grantAgreement/MICINN//BES-2011-047721info:eu-repo/grantAgreement/MICINN//BES-2010-033886https://doi.org/10.1038/s43587-021-00054-2Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2601922026-05-22T06:33:51Z |
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