Amyloid Beta Oligomer Induction of Alzheimer's Disease in Nonhuman Primates

项目总结 阿尔茨海默病(AD)患者会逐渐丧失记忆和认知能力，最终 身体基本功能丧失和死亡。目前，65岁以上的美国人中有11%患有阿尔茨海默病，其发病率和 医疗系统的死亡人数继续上升，产生了重大的社会影响。没有治疗阿尔茨海默病的方法 为了防止其不可避免的进程，开发AD新疗法的一个主要障碍是 现有的临床前建模不足，几乎完全涉及啮齿动物。作为非人类 灵长类与人类在所有方面都比啮齿动物有更大的同源性，包括基因组学和 生理学、认知加工、神经元网络复杂性、白质/灰质比率、 药物/靶点相互作用，以及与年龄相关的病理生理学的触发因素，这是该项目的长期目标 是开发一种新的AD的NHP模型，该模型可以标准化，并在严格、可重复的研究中部署 克服当前在将临床前研究转化为新的临床诊断策略方面的关键缺陷 和治疗。这项申请目的是扩大和推进最近关于一个新的 鞘内注射A-β寡聚体(A-β-Os)的大鼠AD模型。假设是这样的 βOS将触发一系列加速病理，模拟AD大脑中发生的变化 病人。这一假设是基于AD研究领域日益增长的共识，并有强劲的数据支持， AβOs很可能是一种有毒物种，它会在 大脑和突触和神经元的丧失以及相关的认知能力下降。假设将是 通过追求以下两个具体目标，在具有统计意义的设计中进行测试：1)确定 适当的AβO剂量和给药间隔；2)确定诱导的生化和 AβO输注终止后的结构缺陷和AD病理。这些研究将利用活体核磁共振(MRI) 和死后测量(免疫组织化学、生化)以确定AβOS的影响 圣基茨绿猴大脑中的药物，这一物种一直以其 倾向于发展自然发生的AD病理特征。这种方法是创新的，因为它 代表着对当前AD研究范式的实质性转变，并测试了一个新的理论概念。这个 这项研究意义重大，因为它有望通过以下方式克服当前动物AD模型中的严重缺陷 验证散发性AD的加速、可诱导的NHP模型，并允许有效翻译基础研究 转化为新的临床诊断策略和治疗方法。该模型开发计划的成功将 为有需要的学术、生物技术、制药和诊断实验室提供宝贵的资源 为基础研究、诊断和治疗开发提供可靠的AD临床前模型。

PROJECT SUMMARY Patients with Alzheimer's disease (AD) suffer a progressive loss of memory and cognitive ability, and eventual loss of basic bodily functions and death. Currently 11% of Americans over 65 have AD and its incidence and toll on the healthcare system continues to rise with significant societal impact. There are no treatments for AD to prevent its inexorable course, and a principal obstacle to developing new therapies for AD has been the inadequacy of available preclinical modeling, which almost exclusively involves rodents. As nonhuman primates (NHPs) share greater homology to humans than rodents in all respects, including genomics and physiology, cognitive processing, neuronal network complexity, white/gray matter ratios, dynamics of drug/target interactions, and the triggers of age-associated pathophysiology, the long-term goal of this project is to develop a new NHP model of AD that can be standardized and deployed in rigorous, reproducible studies to overcome critical current deficiencies in translating preclinical studies into novel clinical diagnostic strategies and therapies. The objective of this application is to expand and advance recent preliminary work on a new NHP model of AD involving intrathecal administration of amyloid β-oligomers (AβOs). The hypothesis is that AβOs will trigger a cascade of accelerated pathology that mimics the changes occurring in the brains of AD patients. This hypothesis is based on a growing consensus in the AD research field, backed by strong data, that AβOs are likely the toxic species that provoke deposition of the characteristic tangles and plaques in the brain together with loss of synapses and neurons and associated cognitive decline. The hypothesis will be tested in statistically meaningful designs by pursing the following two specific aims: 1) Determine the appropriate dose of AβO and intervals of dosing; and 2) Identify the persistence of induced biochemical and structural deficits and AD pathology following termination of AβO infusion. These studies will utilize in-life (MRI) and post-mortem measurements (immunohistochemistry, biochemistry) to establish the impact of AβOs administration in the brain of the St. Kitts green monkey, a species that has been well characterized for its propensity to develop naturally occurring features of AD pathology. The approach is innovative because it represents a substantial shift from current AD research paradigms and tests a novel theoretical concept. The research is significant because it is expected to overcome critical deficiencies in current animal AD models by validating an accelerated, inducible NHP model of sporadic AD and permit effective translation of basic studies into novel clinical diagnostic strategies and therapies. Success with this model development program would provide a valuable resource to academic, biotechnology, pharmaceutical and diagnostic laboratories in need of a reliable preclinical model of AD for basic research, and diagnostic and therapeutic development.