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

在新型 AD 小鼠模型中研究 APOE 基因型对 AD 病理学的影响

• 批准号: 10301571
• 负责人: Jia Guo
• 金额: $ 20.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301571
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid Beta A4 Precursor Protein; Apolipoprotein E; Behavior; Behavioral; Bioenergetics; Brain; Brain region; Cerebrovascular Circulation; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Communities; Data; Development; Disease susceptibility; Functional Magnetic Resonance Imaging; Funding; Generations; Genes; Genetic; Genotype; Glutamates; Goals; Human; Hyperactivity; Immunohistochemistry; Individual; Japan; Knock-in Mouse; Late Onset Alzheimer Disease; MAPT gene; Magnetic Resonance Spectroscopy; Measurement; Modeling; Morphologic artifacts; Mus; Nerve Degeneration; Neurons; Pathogenesis; Pathologic; Pathology; Pathway interactions; Physiological; Predisposition; Process; Production; Protein Isoforms; Proteins; Regulation; Research; Resistance; Resources; Risk; Role; Running; Series; Structure; System; Techniques; Transgenic Mice; Work; abeta accumulation; aged; base; brain volume; cerebral blood volume; experimental study; gamma-Aminobutyric Acid; genetic risk factor; hTau Mice; mouse model; mutant; novel; novel therapeutic intervention; overexpression; prevent; tau aggregation; theories

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.

项目摘要 载脂蛋白E（APOE）ε4基因的载体有明显增加的阿尔茨海默氏症风险 疾病（AD）。尽管已经提出了许多理论，但这种关联的原因尚不清楚。 我们自己的研究发现了ApoE4表达对大脑重要过程的新型影响， 包括神经元活性，内体 - 溶酶体系统和生物能调节。但是，很大 关于APOE4表达的这些影响仍然存在问题。最重要的是，目前尚不清楚这些影响 以及其他与APOE4相关的途径定义在标志性病理的发展中 在AD患者的大脑中观察到。为了有效地回答这个问题，广告字段需要新的 更忠实地复制AD患者的遗传学和病理学的小鼠模型。作为第一步 这个方向，我们提议生成和表征一种新型的鼠标模型，该模型表达 APOE2，APOE3或APOE4，以及促进人源化突变体应用基因的Ki版本和A 人类Mapt Gene。这些apoe/happ/htau小鼠将使用传统的 实验，例如免疫组织化学（IHC）和行为，以及尖端的结构和 基于功能性MRI（SFMRI）技术。我们预计本文提出的完整研究将导致 创建有价值的新AD鼠标模型，并且表征研究将阐明 差异APOE同工型表达在AD病理的发展及其行为变化上 总的来说，这项研究将是我们寻求了解APOE同工型的重要突破 差异会影响个人对广告的敏感性，有可能导致广告的新治疗策略， 特别是在ApoE4载体中。