BETA-AMYLOID PEPTIDE-DERIVED, OXYGEN-DEPENDENT FREE-RADICALS INHIBIT GLUTAMATE UPTAKE IN CULTURED ASTROCYTES - IMPLICATIONS FOR ALZHEIMERS-DISEASE

beta-AMYLOID (A beta), the central constituent of senile plaques in Al zheimer's disease (AD) brains, was shown by us recently to generate fr ee radicals in an oxygen dependent mechanism. A beta-derived free radi cals were detected directly using electron paramagnetic resonance (EPR ) spin trapping techniques employing the spin trap phenyl-alpha-tert-b utylnitrone (PEN). We have extended these studies to investigate the n ature of the oxyradicals derived from A beta peptides, and we show tha t 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 excito toxic to neurons. These results support the hypothesis that A beta neu rotoxicity in AD may be due in part to A beta-derived, oxygen-dependen t free radical inhibition of glutamate uptake.