beta-Amyloid peptide-derived, oxygen-dependent free radicals inhibit glutamate uptake in cultured astrocytes: implications for Alzheimer's disease.
beta-Amyloid (A beta), the central constituent of senile plaques in Alzheimer's disease (AD) brains, was shown by us recently to generate free radicals in an oxygen dependent mechanism. A beta-derived free radicals were detected directly using electron paramagnetic resonance (EPR) spin trapping techniques employing the spin trap phenyl-alpha-tert-butylnitrone (PBN). We have extended these studies to investigate the nature of the oxyradicals derived from A beta peptides, and we show that these free radicals are able to inhibit glutamate uptake in cultured astrocytes. An implication of inhibited astrocyte glutamate uptake in brain is increased extracellular levels of glutamate, which is excitotoxic to neurons. These results support the hypothesis that A beta neurotoxicity in AD may be due in part to A beta-derived, oxygen-dependent free radical inhibition of glutamate uptake.
Harris
M E
ME
Department of Pharmacology, University of Kentucky, Lexington 40506, USA.
Carney
J M
JM
Cole
P S
PS
Hensley
K
K
Howard
B J
BJ
Martin
L
L
Bummer
P
P
Wang
Y
Y
Pedigo
N W
NW
Butterfield
D A
DA
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D002942:Circular Dichroism; D005609:Free Radicals; D018698:Glutamic Acid / Q000378:metabolism*; D014179:Neurotransmitter Uptake Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D014179:Neurotransmitter Uptake Inhibitors; D018698:Glutamic Acid