The inhibitory effects of beta-amyloid on glutamate and glucose uptakes by cultured astrocytes.
beta-Amyloid is the primary protein component of neuritic plaques, which are degenerative foci in brains of patients with Alzheimer's disease (AD). The effects of this naturally occurring beta-amyloid on the cells of the central nervous system have not been completely understood. beta-Amyloid increases the vulnerability of cultured neurons to glutamate-induced excitotoxic damage. Because astrocytes play a key role in uptake of extracellular glutamate and glutamate uptake is ATP-dependent, we studied the effect of beta25-35 on glutamate and glucose uptake in cultured hippocampal astrocytes following 7 days of exposure to beta25-35. Astrocytic glutamate uptake was studied at 1, 5, 10, 15, 20, and 60 min following the addition of [3H]glutamate (5 nM) to the culture media, and astrocytic glucose uptake was assessed at 60 min after the addition of [14C]glucose (600 and 640 nM) to the media. Glutamate uptake by control astrocytes was time-dependent. Astrocytes exposed to beta25-35, however, showed significantly lower glutamate uptake at all sampling times. Similarly, [14C]glucose uptake by astrocytes was inhibited by beta25-35. When glucose uptake was blocked by phloretin (10 mM), astrocytic [3H]glutamate uptake was also blocked, suggesting that the inhibitory effect of beta-amyloid on glutamate uptake is caused by diminished glucose uptake. Thus, our present study suggests a possible link between two proposed mechanisms of pathogenesis of the Alzheimer's disease: glutamate neurotoxicity and global defect in cerebral energy metabolism.
Parpura-Gill
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Department of Anatomy and Neuroscience Program, Iowa State University, Ames 50011, USA.
Beitz
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D
Uemura
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D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010693:Phloretin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D018698:Glutamic Acid; D005947:Glucose; D010693:Phloretin