Amyloid Beta Oligomer Induction of Alzheimer 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。阿尔茨海默病对医疗保健系统的发病率和死亡人数继续 崛起，具有重大的社会影响。阿尔茨海默病没有治疗方法来防止其不可避免的进程，而 开发阿尔茨海默病新疗法的主要障碍是现有的临床前治疗方法不足 建模，几乎只涉及啮齿类动物。非人灵长类(NHP)与 人类在各个方面都比啮齿动物强，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。鉴于这些翻译优势，长期目标是 这个项目的目的是开发一种新的AD的NHP模型，该模型可以标准化并在严格、 可重复研究，以克服将临床前研究转化为新临床研究中的关键当前缺陷 诊断策略和治疗方法。此应用程序的目标是扩展和推进我们的第一阶段 鞘内注射淀粉样蛋白β寡聚体(A-β-Os)诱导AD动物模型的研究 磷酸化tau蛋白在内侧颞叶皮质记忆回路中的表达增加。这一发现是 与我们的总体假设一致，即βOS将触发模拟的加速病理级联 阿尔茨海默病患者脑内的变化。这一假设是建立在公元前一个日益增长的共识基础上的 研究领域AβOs是引起特征缠结和斑块沉积的有毒物种 伴随着神经元和突触的丧失以及相关的认知能力下降。这一假说将 通过追求三个具体目标在统计上有意义的设计中进一步测试：1)确定范围和 诱发性认知缺陷的持久性；2)使用 药物干预，以及3)评估来自遥测植入物的脑电记录对追踪的有效性 正在进行的AD样病理。这些研究将利用活体生物标志物(MRI确定的海马体体积， 脑脊液分析)和身体测量(免疫组织化学、生化、电子 显微镜)建立AβOS给药对雄性和雌性圣基茨绿鼠脑内的影响 猴子，这一物种的特点很好，因为它倾向于发展自然发生的特征 AD病理学的研究。这种方法是创新的，因为它代表了与当前AD研究的重大转变 例证和检验了一种新的理论概念。这项研究意义重大，因为预计它将1) 通过验证加速的、可诱导的NHP模型，克服当前动物AD模型中的严重缺陷 男性和女性的散发性AD，2)允许将基本发现有效地转化为新的临床 诊断策略和治疗，以及3)帮助了解疾病易感性中可能的性别差异 和进步。这一计划的成功将为需要研究小组提供宝贵的资源 相关、可靠的AD模型，用于基础研究、诊断和治疗开发。

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.