PRESERVATION OF REDOX, POLYAMINE, AND GLYCINE MODULATORY DOMAINS OF THE N-METHYL-D-ASPARTATE RECEPTOR IN ALZHEIMERS-DISEASE

This study used [H-3]dizocilpine ([H-3]MK-801) binding to the N-methyl -D-aspartate (NMDA) receptor to examine redox, polyamine, and glycine modulatory sites in membranes derived from the superior frontal and th e superior temporal cortex of patients with Alzheimer's disease. In co ntrol subjects the competitive polyamine site antagonist arcaine inhib ited [H-3]dizocilpine binding in a dose-dependent fashion and this cur ve was shifted to the right by the addition of 50 mu M spermidine. Arc aine inhibition of binding was more potent in the temporal cortex than in the frontal cortex, in both the absence and presence of 50 mu M sp ermidine. In Alzheimer's disease, arcaine inhibition of [H-3]dizocilpi ne binding (in both the absence and-the presence of spermidine) was no t different from control in either of the two brain areas examined. Th e sulfhydryl redox site of the NMDA receptor was assessed using the ox idizing agent 5,5'-dithio-bis(2-nitrobenzoic acid), which inhibited bi nding in a dose-dependent fashion. This inhibition was similar in pati ents with Alzheimer's disease and control subjects. Glycine-stimulated [H-3]dizocilpine binding was also unaffected in patients with Alzheim er's disease. However, in the temporal cortex there was a significant age-associated decline in [H-3]dizocilpine binding in the presence of 100 mu M glutamate (R(s) = -0.71) and 100 mu M glutamate plus 30 mu M glycine (R(s) = -0.90). There was also an agerelated increase in arcai ne IC50 (which reflects an age-related decrease in arcaine affinity) i n the frontal cortex, determined both in the absence (R(s) = 0.83) and the presence (R(s) = 0.79) of spermidine. These data indicate that th e NMDA receptor and its modulatory redox, polyamine, and glycine subsi tes are intact in patients with Alzheimer's disease and that the modul atory activity of polyamine and glycine sites decline with aging.