Artículo
Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1
Autor/es | March Diaz, Rosana
Lara Ureña, Nieves Romero Molina, Carmen Heras Garvin, Antonio Ortega de San Luis, Clara Alvarez Vergara, Maria I. Navarro Garrido, Victoria Sánchez Mico, María Victoria Vizuete Chacón, María Luisa López Barneo, José Vitorica Ferrández, Francisco Javier Pascual, Alberto |
Departamento | Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica |
Fecha de publicación | 2021 |
Fecha de depósito | 2022-10-18 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | Instituto de Salud Carlos III Ministerio de Educación, Cultura y Deporte (MECD). España Ministerio de Economia, Industria y Competitividad (MINEICO). España Junta de Andalucía |
Identificador del proyecto | CD09/0007
PI18/01556 FPU14/02115 AP2010‐1598 FPU16/02050 FPU15/02898 BES-2010-033886 SAF2012‐33816 SAF2015‐64111‐R SAF2017-90794-REDT PIE13/0004 BFU2016-76872-R BES-2011-047721 P12‐CTS‐2138 P12‐CTS‐2232 UMA18-FEDERJA-211 US‐1262734 |
Cita | March Diaz, R., Lara Ureña, N., Romero Molina, C., Heras Garvin, A., Ortega de San Luis, C., Alvarez Vergara, M.I.,...,Pascual, A. (2021). Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1. Nature Aging, 1 (4), 385-399. https://doi.org/10.1038/s43587-021-00054-2. |
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