Ulas J, Cotman C W
Institute for Brain Aging and Dementia, University of California, Irvine 92697-4540, USA.
Neuroscience. 1997 Aug;79(4):973-82. doi: 10.1016/s0306-4522(97)00023-7.
An antisense oligonucleotide probe was used to examine the expression of gene encoding the obligatory NMDAR1 subunit of the N-methyl-D-aspartate receptor in the hippocampus and adjacent cortical areas (entorhinal and perirhinal cortices) of seven Alzheimer patients and in the same brain regions of seven control individuals. Both groups were matched according to age, sex, cause of death, post mortem delay, and tissue storage time. Densitometric analysis of in situ hybridization autoradiograms revealed a 34% (P<0.05) decrease in NMDAR1 messenger RNA levels in layer III of the entorhinal cortex in Alzheimer brains. Similar deficits. although statistically not significant, were observed in layers II and IV-VI of the entorhinal cortex, and in granule cells of the dentate gyrus. Reduced levels of NMDAR1 messenger RNA were also found in layers II-VI of the perirhinal cortex (41 53% decrease, P<0.02). There were no changes in NMDAR1 messenger RNA expression in the CA1, hilus, or subiculum. Both Alzheimer and control group show substantial intersubject variation in levels of NMDAR1 messenger RNA. The analysis of emulsion-dipped tissue revealed a trend toward a decrease in the number of silver grains overlying individual neurons in the CA1, entorhinal cortex, and granule cell layer of some Alzheimer patients. No significant relationship was detected between the levels of NMDAR1 messenger RNA and post mortem delay, tissue storage, age of the subjects, or mini mental state exam score either in control or Alzheimer individuals. In contrast, a strong inverse correlation between NMDAR1 expression and disease duration was found. These data suggest that reduction in expression of the NMDAR1 gene observed in certain regions of Alzheimer hippocampus and adjacent cortical regions is specific for the disease itself. We postulate that reduced transcript levels may reflect either regional cell loss or anomalies in glutamatergic input to the hippocampus and entorhinal cortex in Alzheimer's disease. When followed by changes at the receptor subunit protein level, altered expression of the NMDAR1 gene in Alzheimer brain may contribute, through the formation of N-methyl-D-aspartate receptors with different properties, to the previously reported modified N-methyl-D-aspartate receptor ligand binding, abnormal vulnerability of select neuronal populations to excitotoxic insult, and may also be involved in learning and memory deficits.
使用反义寡核苷酸探针检测7例阿尔茨海默病患者海马及相邻皮质区域（内嗅皮质和嗅周皮质）以及7例对照个体相同脑区中编码N-甲基-D-天冬氨酸受体必需NMDAR1亚基的基因表达。两组在年龄、性别、死因、死后延迟时间和组织保存时间方面进行了匹配。原位杂交放射自显影片的光密度分析显示，阿尔茨海默病患者脑内嗅皮质III层中NMDAR1信使核糖核酸水平降低了34%（P<0.05）。在内嗅皮质的II层和IV-VI层以及齿状回颗粒细胞中也观察到类似的缺陷，尽管在统计学上不显著。在嗅周皮质的II-VI层中也发现NMDAR1信使核糖核酸水平降低（降低41%-53%，P<0.02）。CA1区、海马门或下托中的NMDAR1信使核糖核酸表达没有变化。阿尔茨海默病组和对照组的NMDAR1信使核糖核酸水平在个体间均存在显著差异。对乳胶浸渍组织的分析显示，一些阿尔茨海默病患者的CA1区、内嗅皮质和颗粒细胞层中，单个神经元上的银颗粒数量有减少的趋势。在对照组或阿尔茨海默病个体中，未检测到NMDAR1信使核糖核酸水平与死后延迟时间、组织保存、受试者年龄或简易精神状态检查评分之间存在显著关系。相反，发现NMDAR1表达与疾病持续时间之间存在强烈的负相关。这些数据表明，在阿尔茨海默病海马及相邻皮质区域某些区域观察到的NMDAR1基因表达降低是该疾病本身所特有的。我们推测，转录水平降低可能反映了阿尔茨海默病中区域细胞丢失或海马和内嗅皮质谷氨酸能输入异常。如果随后受体亚基蛋白水平发生变化，阿尔茨海默病脑中NMDAR1基因表达的改变可能通过形成具有不同特性的N-甲基-D-天冬氨酸受体，导致先前报道的N-甲基-D-天冬氨酸受体配体结合改变、特定神经元群体对兴奋性毒性损伤的异常易感性，还可能与学习和记忆缺陷有关。
