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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/260192
Acceso en línea:http://hdl.handle.net/10261/260192
Access Level:acceso abierto
Palabra clave:Hypoxia
Alzheimer’s disease
Microglia
HIF1
Aerobic respiration
Anaerobic glycolysis
Descripción
Sumario: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.

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