In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid β-peptide and iron: Evidence for a stress response

Zhi Hong Guo, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mild metabolic stress can increase resistance of neurons in the brain to subsequent more severe insults, as exemplified by the beneficial effects of heat shock and ischemic preconditioning. Studies of Alzheimer's disease and other age-related neurodegenerative disorders indicate that dysfunction and degeneration of synapses occur early in the cell death process, and that oxidative stress and mitochondrial dysfunction are central events in this pathological process. It was recently shown that administration of 2-deoxy-D-glucose (2DG), a nonmetabolizable glucose analog that induces metabolic stress, to rats and mice can increase resistance of neurons in the brain to excitotoxic, ischemic, and oxidative injury. We now report that administration of 2DG to adult rats (daily i.p. injections of 100 mg/kg body weight) increases resistance of synaptic terminals to dysfunction and degeneration induced by amyloid β-peptide and ferrous iron, an oxidative insult. The magnitude of impairment of glucose and glutamate transport induced by amyloid β-peptide and iron was significantly reduced in cortical synaptosomes from 2DG-treated rats compared to saline-treated control rats. Mitochondrial dysfunction, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated after exposure to amyloid β-peptide and iron in synaptosomes from 2DG-treated rats. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from 2DG-treated rats, suggesting a mechanism whereby 2DG protects synaptic terminals. We conclude that 2DG bolsters cytoprotectire mechanisms within synaptic terminals, suggesting novel preventative and therapeutic approaches for neurodegenerative disorders. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)173-179
Number of pages7
JournalExperimental Neurology
Volume166
Issue number1
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

Deoxyglucose
Presynaptic Terminals
Amyloid
Glutamic Acid
Iron
Glucose
Peptides
Synaptosomes
Physiological Stress
Neurodegenerative Diseases
Neurons
Ischemic Preconditioning
Brain
Pathologic Processes
Heat-Shock Proteins
Membrane Potentials
Synapses
Shock
Reactive Oxygen Species
Alzheimer Disease

Keywords

  • Alzheimer's disease
  • Amyloid
  • Apoptosis
  • Calorie restriction
  • Cerebral cortex
  • Free radicals
  • Heatshock protein
  • Mitochondria

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

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abstract = "Mild metabolic stress can increase resistance of neurons in the brain to subsequent more severe insults, as exemplified by the beneficial effects of heat shock and ischemic preconditioning. Studies of Alzheimer's disease and other age-related neurodegenerative disorders indicate that dysfunction and degeneration of synapses occur early in the cell death process, and that oxidative stress and mitochondrial dysfunction are central events in this pathological process. It was recently shown that administration of 2-deoxy-D-glucose (2DG), a nonmetabolizable glucose analog that induces metabolic stress, to rats and mice can increase resistance of neurons in the brain to excitotoxic, ischemic, and oxidative injury. We now report that administration of 2DG to adult rats (daily i.p. injections of 100 mg/kg body weight) increases resistance of synaptic terminals to dysfunction and degeneration induced by amyloid β-peptide and ferrous iron, an oxidative insult. The magnitude of impairment of glucose and glutamate transport induced by amyloid β-peptide and iron was significantly reduced in cortical synaptosomes from 2DG-treated rats compared to saline-treated control rats. Mitochondrial dysfunction, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated after exposure to amyloid β-peptide and iron in synaptosomes from 2DG-treated rats. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from 2DG-treated rats, suggesting a mechanism whereby 2DG protects synaptic terminals. We conclude that 2DG bolsters cytoprotectire mechanisms within synaptic terminals, suggesting novel preventative and therapeutic approaches for neurodegenerative disorders. (C) 2000 Academic Press.",
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