Hypoxia compromises the mitochondrial metabolism of Alzheimer's disease microglia via HIF1.
March-Diaz R., Lara-Ureña N., Romero-Molina C., Heras-Garvin A., Ortega-de San Luis C., Alvarez-Vergara MI., Sanchez-Garcia MA., Sanchez-Mejias E., Davila JC., Rosales-Nieves AE., Forja C., Navarro V., Gomez-Arboledas A., Sanchez-Mico MV., Viehweger A., Gerpe A., Hodson EJ., Vizuete M., Bishop T., Serrano-Pozo A., Lopez-Barneo J., Berra E., Gutierrez A., Vitorica J., Pascual A.
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.