The induction of HIF-1 reduces astrocyte activation by amyloid beta peptide.
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 (Abeta)-dependent astrocyte activation leads to a long-term decrease in hypoxia-inducible factor (HIF)-1alpha expression and a reduction in the rate of glycolysis. Glial activation and the glycolytic changes are reversed by the maintenance of HIF-1alpha levels with conditions that prevent the proteolysis of HIF-1alpha. Abeta 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-1alpha 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-1alpha-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.
Schubert
David
D
Cellular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA. schubert@salk.edu
Soucek
Thomas
T
Blouw
Barbara
B
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D046988:Proteasome Endopeptidase Complex; D005947:Glucose; D003676:Deferoxamine