Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor
Early-onset and robust cerebral microvascular accumulation of amyloid β-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid β-protein precursor
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DOI：
10.1074/jbc.m312946200
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发表时间：
2004-05-07
影响因子：
4.8
通讯作者：
Van Nostrand, WE
中科院分区：
文献类型：
--
作者：
Davis, J;Xu, F;Van Nostrand, WE
淀粉样β蛋白（Abeta）的脑血管沉积是阿尔茨海默病和相关疾病的常见病理特征。尤其是荷兰E22 Q和爱荷华州D23 N突变导致家族性脑血管淀粉样变性伴大量弥漫性淀粉样斑块沉积。这两种电荷改变突变都增强了体外Abeta的原纤维形成和致病特性。在这里，我们描述了几个转基因小鼠品系（Tg-SwDI）表达人类神经元Abeta前体蛋白（AbetaPP）窝藏瑞典K670 N/M671 L和血管亲荷兰/爱荷华州E693 Q/D 694 N突变的小鼠Thy1.2启动子的控制下的一代。Tg-SwDI小鼠仅在脑中表达转基因人AbetaPP，但水平低于内源性小鼠AbetaPP的水平。尽管缺乏人AbetaPP的表达，定量酶联免疫吸附测定测量显示，Tg-SwDI小鼠开发的早发性和强大的积累的Abeta在大脑中与分离的脑微血管高度相关。Tg-SwDI小鼠表现出显著的血管周围/血管Abeta沉积，其随年龄显著增加。血管Abeta积聚呈纤维状，表现出强烈的硫磺素S染色，偶尔出现微出血迹象。此外，从3月龄开始观察到大量弥漫性斑块样结构。体内转运研究表明，与野生型Abeta相比，Dutch/爱荷华州突变Abeta更容易保留在脑中。Tg-SwDI小鼠的这些结果表明，人AbetaPP的过表达不是小鼠脑中血管和实质Abeta的早发和稳健积累所必需的。
Cerebrovascular deposition of amyloid beta-protein (Abeta) is a common pathological feature of Alzheimer's disease and related disorders. In particular, the Dutch E22Q and Iowa D23N mutations in Abeta cause familial cerebrovascular amyloidosis with abundant diffuse amyloid plaque deposits. Both of these charge-altering mutations enhance the fibrillogenic and pathogenic properties of Abeta in vitro. Here, we describe the generation of several transgenic mouse lines (Tg-SwDI) expressing human neuronal Abeta precursor protein (AbetaPP) harboring the Swedish K670N/M671L and vasculotropic Dutch/Iowa E693Q/D694N mutations under the control of the mouse Thy1.2 promoter. Tg-SwDI mice expressed transgenic human AbetaPP only in the brain, but at levels below those of endogenous mouse AbetaPP. Despite the paucity of human AbetaPP expression, quantitative enzyme-linked immunosorbent assay measurements revealed that Tg-SwDI mice developed early-onset and robust accumulation of Abeta in the brain with high association with isolated cerebral microvessels. Tg-SwDI mice exhibited striking perivascular/vascular Abeta deposits that markedly increased with age. The vascular Abeta accumulations were fibrillar, exhibiting strong thioflavin S staining, and occasionally presented signs of microhemorrhage. In addition, numerous largely diffuse, plaque-like structures were observed starting at 3 months of age. In vivo transport studies demonstrated that Dutch/Iowa mutant Abeta was more readily retained in the brain compared with wild-type Abeta. These results with Tg-SwDI mice demonstrate that overexpression of human AbetaPP is not required for early-onset and robust accumulation of both vascular and parenchymal Abeta in mouse brain.