The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide.
It is frequently argued that both amyloid beta (Abeta) and oxidative stress are involved in the pathogenesis of Alzheimer's disease (AD). We show here that clonal nerve cell lines and primary cortical neurons that are resistant to Abeta toxicity have an enhanced flux of glucose through both the glycolytic pathway and the hexose monophosphate shunt. AD brain also has increased enzymatic activities in both pathways relative to age-matched controls. The Abeta-induced changes in glucose metabolism are due to the activation of the transcription factor hypoxia inducible factor 1 (HIF-1). As a result of Abeta-induced changes in glucose metabolism, Abeta-resistant cells are more readily killed by glucose starvation and by classes of antipsychotic drugs that inhibit glucose uptake.
Soucek
Thomas
T
The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cumming
Robert
R
Dargusch
Richard
R
Maher
Pamela
P
Schubert
David
D
D000544:Alzheimer Disease / Q000201:enzymology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004351:Drug Resistance; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D005947:Glucose