Systemic and Local Hypoxia Synergize Through HIF1 to Compromise the Mitochondrial Metabolism of Alzheimer's Disease Microglia

Microglial cells are key contributors to Alzheimer’s disease (AD), constituting the first cellular line against As plaques. Local hypoxia and hypoperfusion, which are typically present in peripheral inflammatory foci, are also common in the AD brain. We describe here that As deposits are hypoxic and hypoperfused and that As plaque-associated microglia (AsAM) are characterized by the expression of hypoxia-inducible factor 1 (HIF1)-regulated genes. Notably, AsAM simultaneously upregulate the expression of genes involved in anaerobic glycolysis and oxidative mitochondrial metabolism, show elongated mitochondria surrounded by rough endoplasmic reticulum, and blunt the HIF1-mediated exclusion of pyruvate from the mitochondria through the pyruvate dehydrogenase kinase 1 (PDK1). Overstabilization of HIF1 –by genetic (von Hippel-Lindau deficient microglia) or systemic hypoxia (an AD risk factor)– induces PDK1 in microglia and reduces microglial clustering in AD mouse models. The human AD brain exhibits increased HIF1 activity and a hypoxic brain area shows reduced microglial clustering. The loss of the microglial barrier associates with augmented As neuropathology both in the chronic hypoxia AD mouse model and the human AD brain. Thus, the synergy between local and systemic AD risk factors converges with genetic susceptibility to cause microglial dysfunction.