Beeri R, Le Novère N, Mervis R, Huberman T, Grauer E, Changeux J P, Soreq H
Department of Biological Chemistry, Life Sciences Institute, Hebrew University of Jerusalem, Israel.
J Neurochem. 1997 Dec;69(6):2441-51. doi: 10.1046/j.1471-4159.1997.69062441.x.
In a search for behavioral, neuroanatomical, and metabolic characteristics of Alzheimer's disease that may result from cholinergic malfunction, we used transgenic mice overexpressing acetylcholinesterase (AChE) mRNA and active enzyme in brain neurons. Mapping by in situ hybridization revealed that transgenic and host AChE mRNAs were distributed similarly. In a Morris water maze working memory paradigm, adult transgenic mice did not display the characteristic improvement found in control mice either between or within test days and spent less time than control mice in the platform zone. In 5-week-old transgenic mice, the basilar dendritic trees of layer 5 pyramidal neurons from the frontoparietal cortex were essentially as developed as in age-matched controls. However, branching totally ceased after this age, whereas in control adults it continued up to at least 7 months. Therefore, dendritic arbors became smaller in adult transgenic mice than those of controls. Furthermore, the average number of spines was significantly lower on dendritic branches of 7-month-old but not 5-week-old transgenics as compared with controls. Binding of tritiated hemicholinium-3, a blocker of the high-affinity choline uptake characteristic of active cholinergic terminals, was over twofold enhanced in the brain of transgenic mice. In contrast, no differences were observed in the mRNA and ligand binding levels of several different subtypes of nicotinic and muscarinic acetylcholine receptors. These findings suggest that three different hallmarks associated with Alzheimer's disease--namely, progressive cognitive failure, cessation of dendrite branching and spine formation, and enhanced high-affinity choline uptake--are outcomes of cholinergic malfunction.
为了探寻可能由胆碱能功能障碍导致的阿尔茨海默病的行为、神经解剖学和代谢特征，我们使用了在脑神经元中过表达乙酰胆碱酯酶（AChE）mRNA和活性酶的转基因小鼠。原位杂交图谱显示转基因小鼠和宿主的AChE mRNA分布相似。在莫里斯水迷宫工作记忆范式中，成年转基因小鼠在测试日之间或测试日内均未表现出对照小鼠所具有的特征性改善，且在平台区停留的时间比对照小鼠少。在5周龄的转基因小鼠中，额顶叶皮质第5层锥体神经元的基底树突基本上与年龄匹配的对照小鼠发育程度相同。然而，在此年龄之后分支完全停止，而在对照成年小鼠中，分支至少持续到7个月。因此，成年转基因小鼠的树突分支比对照小鼠的小。此外，与对照相比，7月龄而非5周龄转基因小鼠的树突分支上棘的平均数量显著降低。活性胆碱能终末高亲和力胆碱摄取的阻断剂——氚标记的半胱氨酸-3在转基因小鼠脑中的结合增强了两倍多。相比之下，烟碱型和毒蕈碱型乙酰胆碱受体几种不同亚型的mRNA和配体结合水平未观察到差异。这些发现表明，与阿尔茨海默病相关的三个不同特征——即进行性认知衰退、树突分支和棘形成的停止以及高亲和力胆碱摄取的增强——是胆碱能功能障碍的结果。
