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Keywords:

  • Alzheimer’s disease;
  • amyloid beta peptide;
  • astrocytes;
  • glycolysis;
  • hypoxia-inducible factor;
  • rodents

Abstract

Reduced glucose metabolism and astrocyte activation in selective areas of the brain are pathological features of Alzheimer’s disease (AD). The underlying mechanisms of low energy metabolism and a molecular basis for preventing astrocyte activation are not, however, known. Here we show that amyloid beta peptide (Aβ)-dependent astrocyte activation leads to a long-term decrease in hypoxia-inducible factor (HIF)-1α expression and a reduction in the rate of glycolysis. Glial activation and the glycolytic changes are reversed by the maintenance of HIF-1α levels with conditions that prevent the proteolysis of HIF-1α. Aβ increases the long-term production of reactive oxygen species (ROS) through the activation of nicotinamide adenine dinucleotide phosphate oxidase and reduces the amount of HIF-1α via the activation of the proteasome. ROS are not required for glial activation, but are required for the reduction in glycolysis. These data suggest a significant role for HIF-1α-mediated transcription in maintaining the metabolic integrity of the AD brain and identify the probable cause of the observed lower energy metabolism in afflicted areas. They may also explain the therapeutic success of metal chelators in animal models of AD.