Amyloid Beta Oligomer Induction of Alzheimer Disease in Nonhuman Primates

项目摘要 阿尔茨海默病（AD）患者的记忆和认知能力逐渐丧失，最终 丧失基本的身体功能和死亡。AD在医疗保健系统中的发病率和死亡人数继续增加， 具有重大的社会影响。没有治疗AD的方法来阻止其无情的进程， 开发AD新疗法的主要障碍是可用的临床前药物不足， 建模，这几乎完全涉及啮齿动物。非人灵长类动物（NHP）与 人类在各个方面都比啮齿类动物强，包括基因组学、生理学、认知加工、神经网络 药物/靶标相互作用的复杂性和动力学。鉴于这些转化优势， 该项目的目的是开发一种新的AD NHP模型， 可重复的研究，以克服目前在将临床前研究转化为新的临床研究方面的关键缺陷 诊断策略和治疗。本申请的目的是扩大和推进我们的第一阶段 研究了AD的NHP模型，其中鞘内给予淀粉样蛋白β寡聚体（AβOs）诱导 内侧颞叶皮层记忆回路中磷酸化tau蛋白表达增加。这一发现 这与我们的总体假设一致，即AβOs将引发一系列加速的病理学， 发生在AD患者大脑中的变化。这一假设是基于一个日益增长的共识，在广告 AβOs是一种毒性物质，可引起特征性缠结和斑块的沉积 大脑中的神经元和突触的损失以及相关的认知能力下降。假设将 通过追求三个具体目标，在统计学上有意义的设计中进一步进行测试：1）确定 诱导认知缺陷的持续性; 2）使用 药物干预，以及3）评估遥测植入物的EEG记录的效用，以跟踪 正在进行的AD样病理学。这些研究将利用活体生物标志物（MRI确定的海马体积， CSF分析物）以及尸检测量（免疫组织化学、生物化学、电子显微镜和组织化学）。 以确定AβOs给药对雄性和雌性圣基茨绿色小鼠脑中的影响 猴子，一个物种，已被很好地描述其倾向发展自然发生的特征 AD病理学这种方法是创新的，因为它代表了当前AD研究的实质性转变 范式和测试一个新的理论概念。这项研究意义重大，因为它预计1） 通过验证加速的诱导型NHP模型，克服了当前动物AD模型的严重缺陷 男性和女性中散发性AD的发生率，2）允许将基本发现有效转化为新的临床研究 诊断策略和治疗，以及3）帮助了解疾病易感性的可能性别差异 和进步。该计划的成功将为需要研究的研究小组提供宝贵的资源， 用于基础研究以及诊断和治疗开发的相关、可靠的AD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. The incidence and toll of AD on the healthcare system continues to rise with significant societal impact. There are no treatments for AD to prevent its inexorable course, and the principal obstacle to developing new therapies for AD has been the inadequacy of available preclinical modeling, which almost exclusively involves rodents. Nonhuman primates (NHPs) share greater homology to humans than rodents in all respects, including genomics, physiology, cognitive processing, neuronal network complexity and dynamics of drug/target interactions. Given these translational advantages, 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 our Phase I work on a NHP model of AD in which intrathecal administration of amyloid β-oligomers (AβOs) induces increased expression of phosphorylated tau in the medial temporal cortical memory circuit. This finding is consistent with our overall hypothesis 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 that AβOs are the toxic species that provoke deposition of the characteristic tangles and plaques in the brain together with loss of neurons and synapses and associated cognitive decline. The hypothesis will be tested further in statistically meaningful designs by pursing three specific aims: 1) Determine the extent and persistence of induced cognitive deficits; 2) Confirm the predictive validity of the model using a pharmacological intervention, and 3) Assess the utility of EEG recordings from telemetry implants to track ongoing AD-like pathology. These studies will utilize in-life biomarkers (MRI-determined hippocampal volume, CSF analytes) together with post-mortem measurements (immunohistochemistry, biochemistry, electron microscopy) to establish the impact of AβOs administration in the brain of male and female St. Kitts green monkeys, 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 1) overcome critical deficiencies in current animal AD models by validating an accelerated, inducible NHP model of sporadic AD in both males and females, 2) permit effective translation of basic discoveries into novel clinical diagnostic strategies and therapies, and 3) help understand possible sex differences in disease susceptibility and progression. Success with this program would provide a valuable resource to research groups in need of a relevant, reliable model of AD for basic research, and diagnostic and therapeutic development.