Progressive cognitive impairment and anxiety induction in the absence of plaque deposition in C57BL/6 inbred mice expressing transgenic amyloid precursor protein
Progressive cognitive impairment and anxiety induction in the absence of plaque deposition in C57BL/6 inbred mice expressing transgenic amyloid precursor protein
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DOI：
10.1002/jnr.20127
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发表时间：
2004-05-15
影响因子：
4.2
通讯作者：
Han, PL
中科院分区：
文献类型：
--
作者：
Lee, KW;Lee, SH;Han, PL
许多阿尔茨海默病（AD）的转基因小鼠模型已经被建立，以概括AD脑的组织学发病机制和行为表型。然而，现有的模型都没有表现出AD症状的全谱，也没有开发的动物模型所模仿的所有特征在单个小鼠品系中成功地表现出来，这表明应该探索显示AD样脑的新特征的转基因品系的开发。在这里，我们报告了一个转基因小鼠系，名为TgAPP（Sw，V717 F）/B6，表达人淀粉样前体蛋白（APP）含有瑞典和V717 F印第安纳州突变的近交系C57 BL/6小鼠的大脑，旨在消除潜在的表型变异归因于大多数AD小鼠模型中采用的复合遗传背景。TgAPP（Sw，V717 F）/B6小鼠在杂合子状态下表达的转基因转录物的水平比内源性小鼠APP高2.6 +/-0.1倍。然而，在18月龄的Tg-APP（Sw，V717 F）/B6小鼠的脑中没有产生A β-斑块沉积。在13-15个月时的Tg-APP（Sw，V717 F）/B6小鼠显示出脑中钙结合蛋白和c-Fos的表达减少。11-14个月的Tg-APP（Sw，V717 F）/B6小鼠表现出运动协调性下降，学习和记忆缺陷，焦虑严重增加。在5-7个月的Tg-APP（Sw，V717 F）/B6小鼠中未观察到这些表型。微阵列分析显示，在Tg-APP（Sw，V717 F）/B6小鼠的杏仁核中，先前与焦虑有关的基因的表达发生了变化。综上所述，这些结果表明，转基因APP或其衍生物产生AD样脑的年龄依赖性病理生理学，并且进行性认知障碍和焦虑诱导可以在没有可见的A β斑块沉积的情况下进行。(C)2004 Wiley-Liss，Inc.
Numerous transgenic mouse models for Alzheimer's disease (AD) have been generated to recapitulate the histological pathogenesis and behavioral phenotypes of AD brain. However, none of the existing models exhibits the full spectrum of AD symptoms, nor have all of the traits mimicked by the developed animal models been successfully represented within a single mouse line, indicating that the development of transgenic lines showing new features of the AD-like brain should be explored. Here we report on a transgenic mouse line, named TgAPP (Sw, V717F)/B6, that expresses the human amyloid precursor protein (APP) containing the Swedish and the V717F Indiana mutations in the brains of inbred C57BL/6 mice, designed to eliminate the potential phenotypic variations attributed to the compound genetic backgrounds adopted in most AD mouse models. The TgAPP (Sw, V717F)/B6 mice expressed the transgene transcript, in the heterozygote state, at a level of 2.6 +/- 0.1 fold higher than that of endogenous mouse APP. However, no Abeta-plaque deposition was produced in the brain of the Tg-APP (Sw, V717F)/B6 mice up to 18 months of age. The Tg-APP(Sw, V717F)/B6 mice at 13-15 months showed reduced expression of calbindin and c-Fos in the brain. The Tg-APP (Sw, V717F)/B6 mice at 11-14 months displayed decreased motor coordination, learning and memory deficits, and severely increased anxiety. These phenotypes were not observed in the Tg-APP (Sw, V717F)/B6 mice at 5-7 months. Microarray analysis revealed altered expression, in the amygdala of the Tg-APP (Sw, V717F)/B6 mice, of genes previously implicated in anxiety. Taken together, these results suggest that the transgenic APP, or its derivatives, produces the age-dependent pathophysiology of the AD-like brain and that the progressive cognitive impairment and anxiety induction can proceed in the absence of visible Abeta-plaque deposition. (C) 2004 Wiley-Liss, Inc.