Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.
Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer's disease transgenic mice.
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DOI：
10.1371/journal.pone.0103607
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Torp R
中科院分区：
文献类型：
--
作者：
Nuruddin S;Syverstad GH;Lillehaug S;Leergaard TB;Nilsson LN;Ropstad E;Krogenæs A;Haraldsen IR;Torp R
对阿尔茨海默病（AD）的研究已经表明下丘脑-垂体-性腺（HPG）轴的激素与认知衰老之间的关联，表明HPG轴激素的绝经后/更年期后变化与AD的神经病理学有关。转基因小鼠与AD病理的研究，导致改善了解的病理生理过程的基础AD。本研究的目的是探讨促性腺激素释放激素（Gnrh）及其受体（Gnrhr）的mRNA水平是否在斑块携带阿尔茨海默病转基因小鼠中发生变化，并研究这些水平和淀粉样斑块沉积是否通过促性腺激素释放激素类似物（Gnrh-a;醋酸亮丙瑞林）治疗下调。这项研究是在携带北极和瑞典淀粉样β前体蛋白（AβPP）突变（tgArcSwe）的小鼠中进行的。在12个月大时，雌性tgArcSwe小鼠的Gnrh mRNA水平比年龄匹配的对照组高两倍，Gnrh mRNA水平比年龄匹配的对照组高1.5倍以上。雄性tgArcSwe小鼠表现出相同的变化模式，尽管更明显。在两种性别中，Gnrh-a处理引起Gnrh和Gnrhr mRNA表达的显著下调。免疫组化结合定量图像分析显示，在海马和丘脑中Gnrh-a治疗后斑块负荷没有显著变化。然而，给药雌性小鼠大脑皮质中的斑块负荷往往低于溶剂给药雌性小鼠。本研究指出了AD小鼠模型中激素变化的参与，并表明这些变化可以通过药物治疗有效地抵消。虽然已知在正常衰老中增加，但我们的研究表明，Gnrh/Gnrhr mRNA表达在tgArcSwe小鼠中增加得更显著。醋酸亮丙瑞林治疗成功消除了转基因对Gnrh/Gnrhr mRNA表达的特异性影响。本实验方法应作为进一步研究Gnrh-a治疗在抑制AD斑块发展中的有用性的平台。
Research on Alzheimer's disease (AD) has indicated an association between hormones of the hypothalamic–pituitary–gonadal (HPG) axis and cognitive senescence, indicating that post meno-/andropausal changes in HPG axis hormones are implicated in the neuropathology of AD. Studies of transgenic mice with AD pathologies have led to improved understanding of the pathophysiological processes underlying AD. The aims of this study were to explore whether mRNA-levels of gonadotropin-releasing hormone (Gnrh) and its receptor (Gnrhr) were changed in plaque-bearing Alzheimer's disease transgenic mice and to investigate whether these levels and amyloid plaque deposition were downregulated by treatment with a gonadotropin-releasing hormone analog (Gnrh-a; Leuprorelin acetate). The study was performed on mice carrying the Arctic and Swedish amyloid-β precursor protein (AβPP) mutations (tgArcSwe). At 12 months of age, female tgArcSwe mice showed a twofold higher level of Gnrh mRNA and more than 1.5 higher level of Gnrhr mRNA than age matched controls. Male tgArcSwe mice showed the same pattern of changes, albeit more pronounced. In both sexes, Gnrh-a treatment caused significant down-regulation of Gnrh and Gnrhr mRNA expression. Immunohistochemistry combined with quantitative image analysis revealed no significant changes in the plaque load after Gnrh-a treatment in hippocampus and thalamus. However, plaque load in the cerebral cortex of treated females tended to be lower than in female vehicle-treated mice. The present study points to the involvement of hormonal changes in AD mice models and demonstrates that these changes can be effectively counteracted by pharmacological treatment. Although known to increase in normal aging, our study shows that Gnrh/Gnrhr mRNA expression increases much more dramatically in tgArcSwe mice. Treatment with Leuprorelin acetate successfully abolished the transgene specific effects on Gnrh/Gnrhr mRNA expression. The present experimental approach should serve as a platform for further studies on the usefulness of Gnrh-a treatment in suppressing plaque development in AD.
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影响因子：
3.2
作者：
Gault, PM;Maudsley, S;Lincoln, GA
通讯作者：
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影响因子：
4.2
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120.7
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4.7
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Casadesus G