Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
J Neurosci. 2012 Apr 4;32(14):4803-11. doi: 10.1523/JNEUROSCI.0033-12.2012.
Apolipoprotein E4 (apoE4) plays a major role in the pathogenesis of Alzheimer's disease. Brain amyloid-β (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 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 with 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.
载脂蛋白 E4（apoE4）在阿尔茨海默病的发病机制中起主要作用。脑淀粉样蛋白-β（Aβ）的积累取决于年龄和载脂蛋白 E 同种型（apoE4>apoE3），这在人类和转基因小鼠模型中都是如此。脑 apoE 水平也依赖于同种型，但方向相反（apoE4<apoE3）。因此，一个流行的假设是增加脑 apoE 表达以降低 Aβ 水平。为了验证这一假设，我们生成了表达一个或两个拷贝的人类 APOE3 或 APOE4 基因的突变人类淀粉样前体蛋白转基因小鼠，这些基因被敲入并被 LoxP 位点包围。我们报告说，在 6 个月大的小鼠中，将 apoE3 或 apoE4 表达降低 50%可有效清除 Aβ，并且不会增加 Aβ 积累。然而，与表达两个拷贝的小鼠相比，具有一个拷贝的人类 APOE 基因的 12 个月大的小鼠具有显著降低的 Aβ 水平和斑块负荷，无论表达哪种人类 apoE 同工型，这表明 apoE 在老年小鼠中对 Aβ 积累具有基因剂量依赖性效应。此外，与表达一个或两个拷贝的人类 APOE3 基因的同龄小鼠相比，表达一个或两个拷贝的人类 APOE4 基因的 12 个月大的小鼠具有显著更高的 Aβ 积累和斑块负荷，这表明 apoE 在老年小鼠中对 Aβ 积累具有同工型依赖性效应。此外，在海马星形胶质细胞中进行 Cre 介导的 APOE4 基因切除可显著降低成年小鼠中不溶性 Aβ 的水平。因此，降低 apoE 表达而不是增加其表达是降低脑 Aβ 水平的一种有吸引力的方法。
