Project 3: Multi-modal phenotypic Characterization of marmoset models of Late Onset Alzheimer's Disease

项目总结项目3 项目3：阿尔茨海默病Marmoset模型的比较多模式表型特征 阿尔茨海默病(AD)是导致痴呆的最常见原因，是一种多因素的神经退行性疾病 影响到约600万美国人。目前，没有能够预防、阻止或治疗的干预措施 广告。缺乏足够的动物模型来进行全面的致病研究 阿尔茨海默病的作用机制限制了我们在发现有效治疗方法方面的进展。有一个关键的问题 需要包含遗传可变性、最佳寿命以支持与年龄相关的增强型动物模型 研究，作为人类社会和认知行为的模型的卓越兼容性，以及AD的呈现- 相关病理学。我们联合体的中心前提是：生成、表征和验证 阿尔茨海默病的绒猴模型“(Marmo-AD)是指绒猴将揭示最早的灵长类-- 阿尔茨海默病发生和发展的特定细胞和分子根源。我们推测，绒猴 设计成含有早发性(Eoad)和晚发性AD(LOAD)的遗传风险变异，将揭示临床疾病 模拟人类AD患者的轨迹，并显示灵长类特定的疾病发病机制 通过一个全面的表型表征管道进行检测。我们假设：(1) 遗传、分子、功能、行为和病理表型的综合评估 绒猴将提供有关阿尔茨海默病在人类群体中的起源和发展的可翻译知识；以及 (2)绒猴负荷模型与Eoad模型和Healthy模型的纵向对比研究 控制将确定在坦率的神经病理之前的新出现的表型，并优先处理易处理的目标 未来的治疗发现。鉴定了ATP结合盒A亚家族成员7(ABCA7)基因 通过全基因组关联研究(GWAS)被认为具有最高的优势比之一 人类。在这个项目中，我们将创建一个新的基因工程绒猴负载模型，其中包含一个 ABCA7负载变量。一旦这些动物出生，我们将纵向跟踪它们以识别新出现的动物 与健康衰老背道而驰的表型在出现坦率的神经病理之前。我们将评估 非携带者健康对照绒猴，以表征典型的健康衰老轨迹 建立一个基线，我们可以对照我们的绒猴模型的负荷和Eoad。到时候我们会的 评估ABCA7绒猴负荷模型相对于PSEN1 Eoad模型的疾病轨迹 纵向、多模式的表型特征与AD患者的临床分期一致。通过对比 我们的绒猴模型的Eoad和Load，我们希望识别不同的生物标志物的负载可以 在坦率的神经病理出现之前进行衡量，并确定新的治疗目标的优先顺序 发展。在这些独特的灵长类AD模型得到验证后，我们计划扩大群体并分享这一点 与更大的AD研究社区一起提供宝贵的资源，以帮助加快带来新颖和 对患者进行有效的治疗。

PROJECT SUMMARY PROJECT 3 Project 3: Comparative Multimodal Phenotypic Characterization of Marmoset Models of AD Alzheimer’s Disease (AD), the most common cause of dementia, is a multifactorial neurodegenerative disorder affecting ~6 million Americans. Currently, there are no interventions capable of preventing, stopping, or treating AD. The scarcity of adequate animal models that enable a comprehensive investigation of the pathogenic mechanisms at play in AD has limited our progress towards discovering effective treatments. There is a critical need for enhanced animal models that incorporate genetic variability, optimal lifespan to support age-related research, superior compatibility as a model of human social and cognitive behavior, and the presentation of AD- related pathology. The central premise of our Consortium “Generation, Characterization, and Validation of Marmoset Models of Alzheimer’s Disease” (MARMO-AD) is that the marmoset will reveal the earliest primate- specific cellular and molecular root causes of AD pathogenesis and progression. We postulate that marmosets engineered to harbor genetic risk variants for early- (EOAD) and late-onset AD (LOAD) will reveal clinical disease trajectories that model those of human AD patients and display primate-specific disease pathogenesis that can be detected with a comprehensive phenotypic characterization pipeline. We hypothesize that: (1) the comprehensive assessment of genetic, molecular, functional, behavioral, and pathological phenotypes in marmosets will provide translatable knowledge of the origins and progression of AD in human populations; and (2) the comparative, longitudinal study of the marmoset LOAD model against the EOAD models and healthy controls will identify emerging phenotypes that precede frank neuropathology and prioritize tractable targets for future therapeutic discovery. The ATP-binding cassette, sub-family A, member 7 (ABCA7) gene was identified by genome-wide association studies (GWAS) as having one of the highest odds ratios for developing LOAD in humans. In this project, we will create a novel genetically engineered marmoset LOAD model incorporating an ABCA7 LOAD variant. Once these animals are born, we will follow them longitudinally to identify emerging phenotypes that deviate from healthy aging ahead of the appearance of frank neuropathology. We will evaluate non-carrier healthy control marmosets to characterize the typical healthy aging trajectory across the lifespan and establish a baseline against which we can contrast our marmoset models of LOAD and EOAD. We will then evaluate the disease trajectory of the ABCA7 marmoset LOAD model relative to the PSEN1 EOAD models via longitudinal, multimodal phenotypic characterization in line with the clinical staging of AD patients. By contrasting our marmoset models of EOAD and LOAD, we hope to identify differential biomarkers of LOAD that can be measured ahead of the emergence of frank neuropathology and prioritize novel targets for therapeutic development. Upon validation of these unique primate AD models, we plan to expand the colony and share this precious resource with the greater AD research community to help accelerate the pace of bringing novel and effective treatments to patients.