Investigating the Effects of APOE Genotype on AD Pathology in a Novel AD Mouse Model

项目摘要 载脂蛋白Eε4基因携带者患阿尔茨海默氏症的风险显著增加 疾病(AD)。尽管已经提出了许多理论，但这种联系的原因仍然不清楚。 我们自己的研究发现了APOE4表达对大脑重要过程的新影响， 包括神经元活动、内体-溶酶体系统和生物能量调节。然而，大量的 关于APOE4表达的这些影响，问题仍然存在。最重要的是，目前还不清楚这些措施会产生什么影响 和其他与APOE4相关的途径缺陷对标志性病理的发展有影响 在AD患者的大脑中观察到。为了有效地回答这个问题，AD字段需要新的 更真实地复制AD患者的遗传学和病理学的小鼠模型。作为第一步， 在这个方向上，我们建议生成并表征一种新的鼠标模型，该模型可以表达 APOE2、APOE3或APOE4，以及亲聚的人源化突变APP基因的KI版本和 人类MAPT基因。这些APOE/Happ/hTau小鼠将被老化，并使用传统的 实验，如免疫组织化学(IHC)和行为，以及尖端结构和 基于功能磁共振成像(SfMRI)的技术。我们预计，在此提出的全面研究将导致 创造了一种有价值的新AD小鼠模型，特征研究将阐明 载脂蛋白E亚型差异表达在AD病理发展及行为学改变中的作用 归纳。总而言之，这项研究将是我们在了解载脂蛋白E的异构体方面的重要突破 差异影响个体对AD的易感性，可能导致AD的新治疗策略， 尤其是在APOE4携带者中。

Project Summary Carriers of the apolipoprotein E (APOE) ε4 gene are at a significantly increased risk of developing Alzheimer’s disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. Our own research has uncovered novel effects of APOE4 expression on important processes in the brain, including neuronal activity, the endosomal-lysosomal system and bioenergetic regulation. However, substantial questions remain about these effects of APOE4 expression. Most importantly, it is unclear what effects these and other APOE4-associated pathway deficits have on the development of the hallmark pathologies that are observed in the brains of AD patients. In order to answer this question effectively, the AD field requires new mouse models that more faithfully replicate both the genetics and the pathology of AD patients. As a first step in that direction, we are proposing to generate and characterize a novel mouse model that expresses either the APOE2, APOE3 or APOE4, alongside KI versions of a pro-aggregating humanized mutant APP gene and a human MAPT gene. These APOE/hAPP/hTau mice will be aged and characterized using both traditional experiments, such as immunohistochemistry (IHC) and behavior, as well as cutting-edge structural and functional MRI (sfMRI)-based techniques. We anticipate that the full study proposed herein will result in the creation of a valuable new AD mouse model and that the characterization studies will elucidate the effects of differential APOE isoform expression on the development of AD pathology and the behavioral changes they induce. In total, this study will be an important breakthrough in our quest to understand how APOE isoform differences affect an individual’s susceptibility to AD, potentially leading to new therapeutic strategies for AD, especially among APOE4 carriers.