Rescue of Abeta(1-42)-induced memory impairment in day-old chick by facilitation of astrocytic oxidative metabolism: implications for Alzheimer's disease.
Administration of small oligomeric beta-amyloid (Abeta)(1-42) 45 min before one-trial bead discrimination learning in day-old chicks abolishes consolidation of learning 30 min post-training (Gibbs et al. Neurobiol. Aging, in press). Administration of the beta3-adrenergic agonist CL316243, which specifically stimulates astrocytic but not neuronal glucose uptake, rescues Abeta impaired memory. Weakly reinforced training can be consolidated by various metabolic substrates and we have demonstrated neuronal dependence on oxidative metabolism of glucose soon after training versus astrocytic glucose dependence 20 min later. Based on these findings we examined whether different metabolic substrates were able to counteract memory inhibition by Abeta(1-42). Although lactate, the medium-chain fatty acid octanoate, and the ketone body beta-hydroxybutyrate consolidated weakly reinforced training when injected close to learning, none of them were able to salvage Abeta-impaired memory; at this early time. All three metabolites and the astrocytic-specific acetate consolidated weak learning and rescued Abeta-impaired memory when injected 10-20 min post-training. However, neither glucose nor insulin rescued memory when injected at 20 min. Rescue of memory by providing astrocytes with alternative substrates for oxidative metabolism suggests that Abeta(1-42) exerts its amnestic effects specifically by impairing astrocytic glycolysis.
Gibbs
Marie E
ME
Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. marie.gibbs@med.monash.edu.au
Gibbs
Zoe
Z
Hertz
Leif
L
D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000085:Acetates / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002210:Caprylates / Q000494:pharmacology; D002645:Chickens / Q000502:physiology*; D002952:Citric Acid Cycle / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007657:Ketone Bodies / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D012054:Reinforcement, Psychology
D000085:Acetates; D016229:Amyloid beta-Peptides; D002210:Caprylates; D007004:Hypoglycemic Agents; D007328:Insulin; D007657:Ketone Bodies; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D019344:Lactic Acid; D005947:Glucose; C031492:octanoic acid; D020155:3-Hydroxybutyric Acid