HIF-1α mediates microglial dysfunction and aggravates Alzheimer's disease under hypoxia

Abstract

Brain hypoxia has long been associated with Alzheimer¿s disease but the molecular pathways underlying this interaction are poorly understood. Hypoxia regulates the innate immune system and extensive work has implicated microglia, the brain macrophages, in the pathophysiology of Alzheimer¿s disease. Here we show that hypoxia leads to an acceleration of both Aß peptide accumulation and the downstream neurodegenerative processes. That is associated with a dramatic depletion of microglia surrounding amyloid plaques caused by a reduction of both their number and projections. In vitro, hypoxia leads to microglia cell cycle arrest and impairment of chemotaxis, mimicking the behavior of macrophages under low oxygen levels. HIF1a, a master regulator of the hypoxia responses, mediates the microglial dysfunction under hypoxia. Microglia primed towards a pro-inflammatory Alzheimer-like phenotype exhibit an exacerbated response to hypoxia characterized by the accumulation of HIF1a. Remarkably, AD patients¿ samples present an accumulation of HIF1a that is associated with the progression of the disease. These observations help to explain the association between hypoxia and Alzheimer¿s disease and are relevant to both prevention and therapeutics.