Cell death in Alzheimer’s disease evaluated by DNA fragmentation in situ. Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Alzheimer disease risk genes: 29 and counting. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. The “Big-Bang” for modern glial biology: translation and comments on Pío del Río-Hortega 1919 series of papers on microglia. Intervención de la microglía en los procesos patológicos (células en bastoncito y cuerpos gránulo-adiposos). El ‘tercer elemento’ de los centros nerviosos. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.ĭel Río-Hortega, P. 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. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AβAM clustering and proliferation and increases Aβ neuropathology. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. 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. 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. Nature Aging volume 1, pages 385–399 ( 2021) Cite this article Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1
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