Identification of modifier genes of Alzheimer's disease amyloid pathology using a mouse-to-human translational approach

阿尔茨海默病(AD)是一种常见的、复杂的神经系统疾病，由多种遗传和环境因素引起，使得散发性AD相关基因的识别变得困难。为了克服这些困难，我们结合了Abeta积累和转录的小鼠模型，这简化了复杂性，但增加了这样的遗传筛选的统计能力，并在体内确定Klc1变异体E为Abeta积累修饰物。值得注意的是，这些结果转化为人类，AD患者大脑中KLC1变体E的表达水平显著高于对照组。据我们所知，这是第一个将Klc1剪接与疾病联系起来的报告，并强烈暗示运输缺陷是Abeta积聚和AD病理的主要贡献者。

Alzheimer's disease (AD) is a common, complex neurological disease caused by numerous genetic and environmental factors making the identification of sporadic AD related genes difficult. To overcome these difficulties, we combined a mouse model of Abeta accumulation and transcriptomics, which simplifies the complexity, yet increases the statistical power for such a genetic screen, and identified Klc1 variant E as an Abeta accumulation modifier in vivo. Notably, these results translated to humans where the expression levels of KLC1 variant E in brain were significantly higher in AD than control subjects. To our knowledge, this is the first report linking splicing of Klc1 to disease, and strongly implicates transport defects as a major contributor to Abeta accumulation and AD pathology.