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

项目摘要 载脂蛋白E（APOE）ε4基因携带者患阿尔茨海默病的风险显著增加 疾病（AD）。虽然已经提出了许多理论，但这种关联的原因仍然不清楚。 我们自己的研究已经发现了APOE 4表达对大脑重要过程的新影响， 包括神经元活性、内体-溶酶体系统和生物能调节。然而， 关于APOE 4表达的这些影响仍然存在问题。最重要的是，目前还不清楚这些影响 和其他APOE 4相关通路缺陷对标志性病理学的发展有影响， 在AD患者的大脑中观察到。为了有效地回答这个问题，AD领域需要新的 更忠实地复制AD患者的遗传和病理的小鼠模型。的第一步 在这个方向上，我们建议产生和表征一种新的小鼠模型， APOE 2、APOE 3或APOE 4，以及KI形式的促聚集人源化突变APP基因和 人MAPT基因。这些APOE/hAPP/hTau小鼠将使用传统的 实验，如免疫组织化学（IHC）和行为，以及尖端的结构和 功能性磁共振成像（sfMRI）技术。我们预计，本文提出的全面研究将导致 创建了一种有价值的新AD小鼠模型，表征研究将阐明 APOE亚型的差异表达对AD病理学的发展及其行为学改变的影响， 诱导。总的来说，这项研究将是我们寻求了解APOE亚型 差异影响个体对AD的易感性，可能导致新的AD治疗策略， 尤其是APOE 4携带者。

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.