Hartlage-Rübsamen Maike, Staffa Katharina, Waniek Alexander, Wermann Michael, Hoffmann Torsten, Cynis Holger, Schilling Stephan, Demuth Hans-Ulrich, Rossner Steffen
Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
Int J Dev Neurosci. 2009 Dec;27(8):825-35. doi: 10.1016/j.ijdevneu.2009.08.007. Epub 2009 Aug 21.
Glutaminyl cyclase (QC) converts N-terminal glutaminyl residues into pyroglutamate (pE), thereby stabilizing these peptides/proteins. Recently, we demonstrated that QC also plays a pathogenic role in Alzheimer's disease by generating the disease-associated pE-Abeta from N-terminally truncated Abeta peptides in vivo. This newly identified function makes QC an interesting pharmacological target for Alzheimer's disease therapy. However, the expression of QC in brain and peripheral organs, its cell type-specific and subcellular localization as well as developmental profiles in brain are not known. The present study was performed to address these issues in mice. In brain, QC mRNA expression was highest in hypothalamus, followed by hippocampus and cortex. In liver, QC mRNA concentration was almost as high as in brain while lower QC mRNA levels were detected in lung and heart and very low expression levels were found in kidney and spleen. In the developmental course, stable QC mRNA levels were detected in hypothalamus from postnatal day 5 to 370. On the contrary, in cortex and hippocampus QC mRNA levels were highest after birth and declined during ontogenesis by 20-25%. These results were corroborated by immunocytochemical analysis in mouse brain demonstrating a robust QC expression in a subpopulation of lateral and paraventricular hypothalamic neurons and the labeling of a significant number of small neurons in the hippocampal molecular layer, in the hilus of the dentate gyrus and in all layers of the neocortex. Hippocampal QC-immunoreactive neurons include subsets of parvalbumin-, calbindin-, calretinin-, cholecystokinin- and somatostatin-positive GABAergic interneurons. The density of QC labeled hippocampal neurons declined during postnatal development matching the decrease in QC mRNA expression levels. Subcellular double immunofluorescent analysis localized QC within the endoplasmatic reticulum, Golgi apparatus and secretory granules, consistent with a function of QC in protein maturation and/or modification. Our results are in compliance with a role of QC in hypothalamic hormone maturation and suggest additional, yet unidentified QC functions in brain regions relevant for learning and memory which are affected in Alzheimer's disease.
谷氨酰胺环化酶（QC）可将N端谷氨酰胺残基转化为焦谷氨酸（pE），从而使这些肽/蛋白质稳定。最近，我们证明QC在阿尔茨海默病中也发挥致病作用，它在体内从N端截短的β淀粉样蛋白（Aβ）肽生成与疾病相关的pE-Aβ。这一新发现的功能使QC成为阿尔茨海默病治疗中一个有趣的药理学靶点。然而，QC在脑和外周器官中的表达、其细胞类型特异性和亚细胞定位以及在脑中的发育情况尚不清楚。本研究旨在解决小鼠中的这些问题。在脑中，QC mRNA表达在下丘脑中最高，其次是海马体和皮质。在肝脏中，QC mRNA浓度几乎与脑中一样高，而在肺和心脏中检测到较低的QC mRNA水平，在肾脏和脾脏中发现极低的表达水平。在发育过程中，从出生后第5天到370天，在下丘脑中检测到稳定的QC mRNA水平。相反，在皮质和海马体中，QC mRNA水平在出生后最高，并在个体发育过程中下降20 - 25%。这些结果在小鼠脑中的免疫细胞化学分析中得到证实，该分析表明在下丘脑外侧和室旁神经元亚群中有强烈的QC表达，并且在海马分子层、齿状回门区和新皮质的所有层中标记了大量小神经元。海马体中QC免疫反应性神经元包括小白蛋白、钙结合蛋白、钙视网膜蛋白、胆囊收缩素和生长抑素阳性的GABA能中间神经元亚群。在出生后发育过程中，QC标记的海马体神经元密度下降，与QC mRNA表达水平的下降相匹配。亚细胞双重免疫荧光分析将QC定位在内质网、高尔基体和分泌颗粒中，这与QC在蛋白质成熟和/或修饰中的功能一致。我们的结果符合QC在促甲状腺激素释放激素成熟中的作用，并提示在与学习和记忆相关的脑区中存在尚未明确的QC功能，而这些脑区在阿尔茨海默病中会受到影响。
