Modeling Alzheimer's Disease Related Dementias in the Marmoset

摘要 该项目的长期目标是在更长的寿命中模拟阿尔茨海默病相关痴呆(ADRD) 哺乳动物。这些多维哺乳动物ADRD模型，包括额颞部退行性变(FTD)， 路易体痴呆(LBD)、血管对认知损害和痴呆的贡献(VCID)以及混合 病因学痴呆症，旨在向人类ADRD提供疾病相关阶段的信息，并作为 用于研究疾病机制和确定治疗靶点的工具。ADRD的发展是由于 在大脑中长时间发生的一系列复杂事件--前驱阶段可能会持续 人类在10-20年后--在临床被诊断为痴呆症之前。了解这一早期阶段将是 对于开发诊断工具(例如，神经成像)和筛选化合物至关重要 预防或改变人类的疾病进展。已经开发了各种ADRD小鼠模型来 进一步研究潜在的分子和细胞机制，以确定治疗靶点，并 测试治疗候选药物。虽然现有的ADRD鼠标模型已经实现了这三个方面的每一个进展 目标，到目前为止可用的那些并没有概括分子的全部光谱和复杂性， 典型痴呆的细胞、行为和认知病理学观察。有几行证据表明 绒猴已经成为基础神经科学和翻译神经科学的非人类灵长类动物模型 来弥合老鼠和人类之间的鸿沟。首先，绒猴和人类在以下方面的复杂性非常相似 大脑结构、认知/社会行为、新陈代谢和免疫功能。第二，AS 与其他灵长类动物相比，它在理解大脑功能和 临床前试验，因为它们寿命短，体型小，繁殖力高。最后，一个 一套基因编辑工具可用于生成各种类型的转基因绒猴。几行 一系列证据使我们阐明了在髓系细胞2(TREM2)上表达的触发受体的作用 ADRD中的路径。首先，纯合的TREM2零突变与隐性早发有关 痴呆症称为纳苏-哈科拉病。几个TREM2变种是FTD的病理性变化和一个主要的 AD、帕金森氏病和肌萎缩侧索硬化症的危险因素/修饰者(见 Https://www.alzforum.org/mutations/trem2).TREM2突变加速血管改变和 血脑屏障损害并可能导致VCID。第二，小胶质细胞已经成为一种关键的细胞类型 在维持中枢神经系统内稳方面，TREM2介导了多个关键的 信号通路。第三，老龄化是ADRD的主要风险因素。TREM2在衰老过程中的表达降低 可能会加速ADRD的发展。加在一起 ，TREM2有望影响神经元和血管 与开发多种形式的ADRD相关的系统。为了阐明TREM2在ADRD中的作用， 将产生不同的转基因绒猴，并对其进行表征。

Abstract The long-term goal of this project is to model Alzheimer's Disease related dementias (ADRD) in longer-living mammals. These multi-dimensional mammalian ADRD models, including frontotemporal degeneration (FTD), Lewy body dementia (LBD), vascular contributions to cognitive impairment and dementia (VCID), and mixed etiology dementias, are aimed at informing human ADRD across the disease-relevant stages and serve as tools to interrogate disease mechanisms and identify therapeutic targets. ADRD develops as a result of a complex series of events that take place in the brain over a long period of time—the prodromal phase can last 10-20 years in humans—before dementia is clinically diagnosed. Understanding this EARLY stage will be critically important for developing diagnostic tools (e.g., neuroimaging) and for screening compounds to prevent or modify disease progression in humans. A variety of ADRD mouse models have been developed to advance research into the underlying molecular and cellular mechanisms, to identify therapeutic targets, and to test therapeutic candidates. While existing ADRD mouse models have enabled progress toward each of these objectives, those available to date do not recapitulate the full spectrum and complexity of the molecular, cellular, behavioral and cognitive pathology observed in typical dementias. Several lines of evidence suggest that marmosets have emerged as a non-human primate model for both basic and translational neuroscience to bridge the gap between mice and humans. First, marmosets and humans have very similar complexity in brain structures, cognitive/social behavioral repertoires, metabolisms and immune functions. Second, as compared to other primates, it is highly economical and scalable for understanding brain functions and preclinical tests because they have a short lifespan, small body size, and high reproductive power. Finally, a set of gene editing tools is available to generate various types of genetically modified marmosets. Several lines of evidence led us to elucidate the role of the triggering receptor expressed on myeloid cells 2 (TREM2) pathways in ADRD. First, homozygous TREM2 null mutations have been linked to a recessive early-onset dementia syndrome called Nasu–Hakola disease. Several TREM2 variants are pathologic to FTD and a major risk factor/modifier for AD, Parkinson's disease, and amyotrophic lateral sclerosis (see https://www.alzforum.org/mutations/trem2). TREM2 mutation precipitates changes in vascular changes and blood brain barrier damages and may contribute to VCID. Second, microglia have emerged as a key cell type in the maintenance of central nervous system homeostasis, for which TREM2 mediates multiple critical signaling pathways. Third, aging is a major risk factor for ADRD. Decreased TREM2 expression during aging may accelerate ADRD development. Taken together , TREM2 is poised to influence neuronal and vascular systems associated with the development of multiple forms of ADRD. To elucidate the role of TREM2 in ADRD, different genetically modified marmosets will be generated and characterized.