Ułas J, Brunner L C, Nguyen L, Cotman C W
Irvine Research Unit in Brain Aging, University of California, Irvine 92717-4550.
Neuroscience. 1993 Feb;52(4):843-54. doi: 10.1016/0306-4522(93)90533-l.
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.
在阿尔茨海默病患者及年龄匹配的对照者的海马体和海马旁回中，研究了与腺苷A1受体的结合及其与G蛋白偶联的状态。将A1受体的结合情况与N-甲基-D-天冬氨酸受体复合物通道相关位点（用（+）-[3H]5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐标记）的结合情况进行了比较。体外定量放射自显影显示，在老年对照者的大脑中，用激动剂（（-）-[3H]苯异丙基腺苷）或拮抗剂（[3H]8-环戊基-1,3-二丙基黄嘌呤）标记的A1受体具有相似的解剖分布。在阿尔茨海默病患者中，齿状回分子层中激动剂和拮抗剂结合位点的密度均显著降低。在海马旁回的CA1原层和外层也观察到A1激动剂结合减少，而在海马下托和CA3区发现拮抗剂结合减少。在CA1区和海马旁回中发现N-甲基-D-天冬氨酸受体通道位点的密度降低。腺苷A1和N-甲基-D-天冬氨酸受体结合减少是由于结合位点密度（Bmax）降低，而非受体亲和力（KD）改变。在老年对照者和阿尔茨海默病受试者中，GTP均显著降低了A1激动剂结合位点的密度，同时KD值升高，而拮抗剂结合不受GTP影响。结果表明，腺苷A1受体激动剂和拮抗剂识别重叠的结合位点群体。齿状回分子层中A1受体密度降低很可能反映了阿尔茨海默病中穿通通路输入的损伤，而CA1和CA3区结合的改变可能是由于内在神经元的丧失。GTP对对照者和阿尔茨海默病患者A1受体结合的类似影响表明，阿尔茨海默病中A1受体与G蛋白的偶联没有改变，从而支持了阿尔茨海默病中受体与其效应系统正常偶联的观点。
