Modeling the Genetic Interaction Between Klotho and APOE Alleles in Alzheimer's Disease

项目摘要 了解遗传风险因素的组合如何影响迟发性阿尔茨海默病（LOAD）的风险 可以引导出有针对性的治疗干预策略。载脂蛋白E4（APOE 4），一种常见的 APOE是发生LOAD的单一最大遗传风险因素。APOE 4状态与增加 LOAD患者中的炎症和较高的β-淀粉样蛋白负荷。尽管遗传风险增加，APOE 4 载体在其寿命期间并不总是产生LOAD。几项大规模的遗传学研究 确定了一种常见的单倍型的老化因子klotho，改变发病年龄和减少淀粉样斑块 在APOE 4载体中特异性沉积，这表明klotho变体可以提供抗APOE 4的保护作用。 通过抵消APOE 4的负面影响来发展LOAD。在人类中，克洛索有两个 常见的错义变体（rs 9536314，p.F352V; rs 9527025，p.C370S）。这两种编码的组合 变体定义了klotho V/S（KL-V/S）单倍型，该单倍型在APOE 4携带者中对LOAD具有保护作用， Klotho F/C（KL-F/C）单倍型，其对LOAD无保护作用。本建议的总体目标是 确定klotho改变的生理过程，作为LOAD中的APOE 4特异性保护因子，使用 一组最近创建的小鼠模型，包含klotho和 APOE。我们的中心假设是，保护性KL-V/S单倍型将显著延迟年龄依赖性的 而参考KL-F/C单倍型将不能减弱这些标志 加载病理。我们将评估多个负载相关的结果，以验证和表征这种klotho- APOE遗传互作有三个具体目的：（1）确定klotho单倍型对年龄相关的 小鼠血液和CSF中的虚弱和klotho同种型水平;（2）测定LOAD标志病理学的变化 由小鼠中klotho和APOE等位基因之间的相互作用驱动;以及（3）鉴定共享的分子特征 在通过klotho单倍型分层的人LOAD和新型klotho小鼠模型中。这项工作的成果将 导致人类klotho单倍型的新小鼠模型的表征，并鉴定 受klotho变异体的影响差异显著，呈APOE依赖性。这些信息将提供一个 在人类遗传学研究中观察到的上位相互作用的生物学基础，从而提供了必要的 功能信息，以指导基于KL-V/S保护APOE 4携带者的潜在治疗。

PROJECT SUMMARY Understanding how combinations of genetic risk factors influence risk for late-onset Alzheimer’s disease (LOAD) can lead to targeted strategies for therapeutic intervention. Apolipoprotein E4 (APOE4), a common variant of APOE, is the single largest genetic risk factor for developing LOAD.APOE4 status is linked to increased inflammation and higher β-amyloid burden in LOAD patients. Despite this increased genetic risk profile, APOE4 carriers do not always develop LOAD in the course of their lifetime. Several large-scale genetic studies have identified a common haplotype of the aging factor klotho that modify age of onset and reduce amyloid plaque deposition specifically in APOE4 carriers, suggesting that klotho variants can provide a protective effect against the development of LOAD by counteracting the negative effects of APOE4. In humans, klotho harbors two common missense variants (rs9536314, p.F352V; rs9527025, p.C370S). The combination of these two coding variants define the klotho V/S (KL-V/S) haplotype, which is protective against LOAD in APOE4 carriers, and the klotho F/C (KL-F/C) haplotype, which is not protective against LOAD. The overall objective of this proposal is to determine the physiological processes altered by klotho as an APOE4-specific protective factor in LOAD using a set of recently-created mouse models harboring combinations of relevant human variants in both klotho and APOE. Our central hypothesis is that the protective KL-V/S haplotype will significantly delay age-dependent inflammation and amyloid deposition while the reference KL-F/C haplotype will fail to attenuate these hallmark LOAD pathologies. We will assess multiple LOAD-relevant outcomes to validate and characterize this klotho- APOE genetic interaction with three specific aims: (1) Determine the effects of klotho haplotypes on age-related frailty and klotho isoform levels in blood and CSF in mice; (2) Determine changes in LOAD hallmark pathologies driven by the interaction between klotho and APOE alleles in mice; and (3) Identify molecular signatures shared in human LOAD stratified by klotho haplotype and the novel klotho mouse models. The outcome of this work will result in the characterization of new mouse models of human klotho haplotypes and identify the pathways which are differentially affected by klotho variants in an APOE-dependent manner. This information will provide a biological basis for the epistatic interaction observed in human genetic studies, thereby providing the necessary functional information to guide potential treatments based on KL-V/S protection for APOE4 carriers.