Modeling Frontotemporal Dementia in Rhesus Macaques

摘要 额颞叶痴呆（Frontotemporal dementia，FTD）是一种与阿尔茨海默病（Alzheimer's disease，AD）相关的痴呆，可伴或不伴帕金森综合征 （ADRD）与MAPT基因的散发性和家族性突变有关，包括常染色体 显性R406 W错义点突变。FTD MAPT R406 W患者出现进行性记忆丧失， 以及迟发性帕金森症、人格改变和/或语言缺陷。典型病理学发现 包括磷酸化tau蛋白丝异常神经元内积累（tau蛋白病），额颞 萎缩、神经元损失和神经胶质增生。在威斯康星州国家灵长类动物研究中心， 与贝勒医学院合作，一只恒河猴被确定为MAPT R406 W的携带者 突变与人类患者相同FTD生物标志物和治疗方法的开发进展， 其他痴呆症的研究由于缺乏可靠的动物模型而受到阻碍。非人灵长 （NHP），特别是恒河猴，是研究痴呆症和相关神经变性的理想物种， 因为它们的行为和神经解剖学很复杂。在本申请的R61阶段，我们提出 对该家族的MAPT R406携带者进行表型分析并鉴定额外的MAPT R406 W突变 载波恒河猴将接受一系列与年龄相适应的行为测试（认知、情绪和 运动）、MRI（用于神经解剖学和体积分析）和F18-MK 6240 PET（用于可视化tau积聚） 并与年龄和性别匹配的对照组进行比较。这些动物将是一个繁殖群体的创始人， MAPT R406 W载体。在R33阶段，我们的目标是创建MAPT R406 W恒河猴群资源， 通过培育突变的恒河猴并从携带者的骨髓中产生诱导多能干细胞（iPSC）， 成纤维细胞将对后代进行基因分型和神经行为评价。iPSC将成为一个平台， 研究ADRD等位基因对体外神经分化的影响。该项目的总体目标是 为ADRD研究社区生成NHP资源。遗传FTD的一个良好表征的NHP模型， 通过体内行为和成像结果测量以及相关的iPSC系的支持，将有助于理解 疾病的病理机制，这可能导致生物标志物的鉴定和治疗 目标的我们组建了一支强大的跨学科研究团队，专注于翻译 神经科学和神经退行性疾病，人类和非人类灵长类遗传学，干细胞，以及大多数 重要的是，专家们致力于非人类灵长类动物的繁殖和护理。

ABSTRACT Frontotemporal dementia (FTD) with or without parkinsonism, is an Alzheimer’s disease related dementia (ADRD) that has been linked to sporadic and familial mutations in the MAPT gene, including the autosomal dominant R406W missense point mutation. Patients with FTD MAPT R406W present progressive memory loss, and late-onset of parkinsonism, personality changes, and/or language deficits. Typical pathological findings include abnormal intraneuronal accumulation of phosphorylated tau filaments (tauopathy), frontotemporal atrophy, neuronal loss, and gliosis. At the Wisconsin National Primate Research Center (WNPRC) in collaboration with Baylor College of Medicine, a rhesus monkey was identified as a carrier of the MAPT R406W mutation, identical to human patients. Progress in the development of biomarkers and treatments for FTD and other dementias has been hampered by the lack of faithful animal models of the disorder. Nonhuman primates (NHPs), in particular rhesus macaques, are an ideal species to study dementias and related neurodegeneration, due to the complexity of their behavior and neuroanatomy. In the R61 phase of this application we propose to phenotype the MAPT R406 carriers of this family and to identify additional MAPT R406W mutation carriers. The rhesus will be evaluated with a battery of age-appropriate behavioral tests (cognitive, mood and motor), MRI (for neuroanatomical and volumetric analysis) and F18-MK6240 PET (to visualize tau accumulation) and compared to age- and sex- matched controls. These animals will be the founders of a breeding colony of MAPT R406W carriers. During the R33 phase we will aim to create a MAPT R406W rhesus colony resource, by breeding the mutated rhesus and generating induced pluripotent stem cells (iPSCs) from the carriers’ fibroblasts. The offspring will be genotyped and neurobehaviorally evaluated. The iPSCs will be a platform to study the effects of ADRD alleles on in vitro neural differentiation. The overarching goal of this project is to generate an NHP resource for the ADRD research community. A well characterized NHP model of genetic FTD, supported by in vivo behavioral and imaging outcome measures and associated iPSC lines, will help understand the pathological mechanisms of the disease, which could lead to the identification of biomarkers and therapeutic targets. We have assembled a strong team of investigators across different disciplines focused on translational neuroscience and neurodegenerative diseases, human and nonhuman primate genetics, stem cells, and, most importantly, experts devoted to nonhuman primate breeding and care.