Reduced density of adenosine A1 receptors and preserved coupling of adenosine A1 receptors to G proteins in Alzheimer hippocampus: a quantitative autoradiographic study.
Binding to adenosine A1 receptors and the status of their coupling to G proteins were studied in the hippocampus and parahippocampal gyrus of Alzheimer individuals and age-matched controls. The binding to A1 receptors was compared with binding to the N-methyl-D-aspartate receptor complex channel-associated sites (labeled with (+)-[3H]5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine maleate). In vitro quantitative autoradiography demonstrated a similar anatomical distribution of A1 receptors labeled either with an agonist ((-)-[3H]phenylisopropyladenosine) or antagonist ([3H]8-cyclopentyl-1,3-dipropylxanthine) in the brains of elderly controls. In Alzheimer patients, significant decreases in the density of both agonist and antagonist binding sites were found in the molecular layer of the dentate gyrus. Decreased A1 agonist binding was also observed in the CA1 stratum oriens and outer layers of the parahippocampal gyrus, while reduced antagonist binding was found in the subiculum and CA3 region. Reduced density of the N-methyl-D-aspartate receptor channel sites was found in the CA1 region and parahippocampal gyrus. The reductions in binding to adenosine A1 and N-methyl-D-aspartate receptors were due to a decrease in the density of binding sites (Bmax), and not changes in receptor affinity (KD). In both elderly control and Alzheimer subjects, GTP substantially reduced the density of A1 agonist binding sites with a concomitant increase in the KD values, whereas antagonist binding was unaffected by GTP. The results suggest that adenosine A1 receptor agonists and antagonists recognize overlapping populations of binding sites. Reduced density of A1 receptors in the molecular layer of the dentate gyrus most probably reflects damage of the perforant path input in Alzheimer's disease, while altered binding in the CA1 and CA3 regions is probably due to loss of intrinsic neurons. Similar effects of GTP on binding to A1 receptors in control and Alzheimer individuals suggest lack of alterations in coupling of A1 receptors to G proteins in Alzheimer's disease, thus supporting the notion of normal receptor coupling to their effector systems in Alzheimer's disease.
Ułas
J
J
Irvine Research Unit in Brain Aging, University of California, Irvine 92717-4550.
Brunner
L C
LC
Nguyen
L
L
Cotman
C W
CW
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001345:Autoradiography; D016291:Dizocilpine Maleate / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008297:Male; D009928:Organ Specificity; D011712:Pyramidal Tracts / Q000378:metabolism / Q000648:ultrastructure; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011983:Receptors, Purinergic / Q000032:analysis / Q000378:metabolism*; D014316:Tritium; D014970:Xanthines / Q000378:metabolism
D016194:Receptors, N-Methyl-D-Aspartate; D011983:Receptors, Purinergic; D014970:Xanthines; D014316:Tritium; C027513:N(6)-cyclohexyladenosine; D016291:Dizocilpine Maleate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D019204:GTP-Binding Proteins; D000241:Adenosine