Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice.
Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice.
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DOI：
10.1523/jneurosci.0033-12.2012
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发表时间：
2012-04-04
期刊：
影响因子：
--
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
Bien-Ly N;Gillespie AK;Walker D;Yoon SY;Huang Y
载脂蛋白（apo）E4在阿尔茨海默病（AD）的发病机制中起主要作用。在人类和转基因小鼠模型中，脑内β -淀粉样蛋白（Aβ）的积累取决于年龄和载脂蛋白E异构体（apoE4＞apoE3）。脑内载脂蛋白E水平也依赖于异构体，但方向相反（apoE4＜apoE3）。因此，一个流行的假设是增加脑内载脂蛋白E的表达以降低Aβ水平。为了验证这一假设，我们培育了表达一个或两个拷贝的人载脂蛋白E3或载脂蛋白E4基因的突变型人淀粉样前体蛋白（hAPP）转基因小鼠，这些基因被敲入并两侧带有LoxP位点。我们报告称，在6个月大的小鼠中使apoE3或apoE4表达降低50%可有效清除Aβ，且不会增加Aβ的积累。然而，与具有两个拷贝的小鼠相比，具有一个拷贝人载脂蛋白E基因的12个月大的小鼠无论表达哪种人载脂蛋白E异构体，其Aβ水平和斑块负荷都显著降低，这表明载脂蛋白E对老年小鼠Aβ积累具有基因剂量依赖性影响。此外，表达一个或两个拷贝人载脂蛋白E4基因的12个月大的小鼠比表达一个或两个拷贝人载脂蛋白E3基因的同龄小鼠具有显著更高的Aβ积累水平和斑块负荷，这表明载脂蛋白E对老年小鼠Aβ积累具有异构体依赖性影响。而且，在海马星形胶质细胞中Cre介导的apoE4基因切除显著降低了成年小鼠的不溶性Aβ。因此，降低而非增加载脂蛋白E的表达是降低脑内Aβ水平的一种有吸引力的方法。
Apolipoprotein (apo) E4 plays a major role in the pathogenesis of Alzheimer’s disease (AD). Brain amyloid-beta (Aβ) accumulation depends on age and apoE isoforms (apoE4 > apoE3) both in humans and in transgenic mouse models. Brain apoE levels are also isoform-dependent, but in the opposite direction (apoE4 < apoE3). Thus, one prevailing hypothesis is to increase brain apoE expression to reduce Aβ levels. To test this hypothesis, we generated mutant human amyloid precursor protein (hAPP) transgenic mice expressing one or two copies of the human apoE3 or apoE4 gene that was knocked-in and flanked by LoxP sites. We report that reducing apoE3 or apoE4 expression by 50% in 6-month-old mice results in efficient Aβ clearance and does not increase Aβ accumulation. However, 12-month-old mice with one copy of the human apoE gene had significantly reduced Aβ levels and plaque loads compared to mice with two copies, regardless of which human apoE isoform was expressed, suggesting a gene dose-dependent effect of apoE on Aβ accumulation in aged mice. Additionally, 12-month-old mice expressing one or two copies of the human apoE4 gene had significantly higher levels of Aβ accumulation and plaque loads than age-matched mice expressing one or two copies of the human apoE3 gene, suggesting an isoform-dependent effect of apoE on Aβ accumulation in aged mice. Moreover, Cre-mediated apoE4 gene excision in hippocampal astrocytes significantly reduced insoluble Aβ in adult mice. Thus, reducing, rather than increasing, apoE expression is an attractive approach to lowering brain Aβ levels.