Hypoxia compromises the mitochondrial metabolism of Alzheimer’s disease microglia via HIF1

Abstract

Increasing evidence implicates the decline of microglial defensive responses in the progression of Alzheimer's disease (AD). Loss of function of genetic non-modifiable AD risk factors, as the triggering receptor expressed on myeloid cells 2 (TREM2) and the apolipoprotein E (APOE), associates with microglial dysfunction characterized by reduced clustering and survival around Aß plaques. However, the contribution of modifiable AD risk factors to microglial dysfunction is not known. We show here the concomitant activation of the HIF1-mediated stress response pathway and the transcription of aerobic respiration-related genes in Aß plaque-associated microglia (AßAM). We also demonstrate that AßAM mitochondria are elongated, a cellular response found in cells that maintain aerobic respiration under low nutrient and oxygen conditions, suggesting that HIF1 activation may be hijacking microglial mitochondrial metabolism.Overactivation of HIF1 induces microglial quiescence in cellulo, characterized by lower mitochondrial respiration and reduced proliferation. In vivo, overstabilization of HIF1, either genetically (von Hippel-Lindau deficient microglia) or by exposure to systemic hypoxia (mimicking vascular contributions to AD), reduces AßAM clustering and proliferation. We also observed increased Aß neuropathology in an AD mouse model exposed to hypoxia that mimics the loss of function of genetic AD risk genes. In the AD hippocampus, the upregulation of HIF1a and HIF1 target genes correlates with the presence of "nude" plaques (i.e., with reduced microglial coverage) in a hypoxia-prone brain area and the increase of Aß plaque-associated dystrophic neurites. Thus, low oxygen levels, a modifiable AD risk factor, disrupt microglial mitochondrial metabolism and converge with genetic susceptibility to cause AD microglial dysfunction.