Amyloid Beta Oligomer Induction of Alzheimer Disease in Nonhuman Primates

β淀粉样蛋白寡聚体在非人灵长类动物中诱导阿尔茨海默病

基本信息

批准号：
10249326
负责人：
MICHAEL R WEED
金额：
$ 77.08万
依托单位：
VIRSCIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249326
关键词：
Address Affect African Green Monkey Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy American Animal Model Animals Appearance Autopsy Basic Science Biochemistry Biological Assay Biological Markers Blood Body Temperature Brain Brain scan Cerebrospinal Fluid Cessation of life Characteristics Circadian Dysregulation Clinical Trials Cognition Cognitive Cognitive deficits Computers Consensus Data Deposition Development Diagnostic Disease Disease Progression Disease susceptibility Dose Drug Targeting Early Diagnosis Electroencephalography Electron Microscopy Electrophysiology (science)Endocrinology Failure Female Fostering Frequencies Genetic Genomics Goals Grant Healthcare Systems Hippocampus (Brain)Human Immunohistochemistry Immunology Impaired cognition Implant Incidence Industry Institutes Intervention Intrathecal Injections Lead Life Magnetic Resonance Imaging Measurement Measures Medial Memory Memory Loss Mission Modeling Monkeys Morbidity - disease rate Mus National Institute of Allergy and Infectious Disease National Institute of Biomedical Imaging and Bioengineering National Institute of Environmental Health Sciences National Institute of Mental Health National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurofibrillary Tangles Neurons Pathologic Pathology Patients Pattern Performance Pharmaceutical Preparations Pharmacology Phase Physiology Play Pre-Clinical Model Preclinical Testing Prefrontal Cortex Public Health Rattus Reproducibility Research Resources Risk Rodent Role Sampling Senile Plaques Severities Sex Differences Sleep Standardization Symptoms Synapses System Telemetry Testing Time Touch sensation Training Translating Translations United States National Institutes of Health Work abeta oligomer awake base brain tissue circadian clinical diagnostics clinical efficacy cognitive ability combat commercialization cost effective design disability effective therapy functional restoration improved innovation liraglutide male model development mouse model neuron loss nonhuman primate novel novel diagnostics novel strategies novel therapeutic intervention novel therapeutics pharmacokinetics and pharmacodynamics preclinical study prevent prodromal Alzheimer&apos s disease programs research and development response sex stem subcutaneous success symptom treatment tau-1 telemetering therapeutic development therapeutically effective translational model treatment strategy

项目摘要

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.

项目概要阿尔茨海默病 (AD) 患者的记忆力和认知能力逐渐丧失，最终 AD 的发病率和医疗系统造成的死亡人数持续上升。 AD 的发病率上升并具有重大的社会影响，目前尚无治疗 AD 的方法可以阻止其不可阻挡的进程。开发 AD 新疗法的主要障碍是现有临床前研究的不足模型几乎完全涉及非人类灵长类动物（NHP），与它们具有更大的同源性。人类在各个方面都优于啮齿动物，包括基因组学、生理学、认知处理、神经网络考虑到这些转化优势，药物/靶点相互作用的复杂性和动态性是长期目标。该项目的目的是开发一种新的 NHP AD 模型，该模型可以标准化并在严格的、可重复的研究，以克服当前将临床前研究转化为新的临床研究的关键缺陷该应用的目的是扩大和推进我们的第一阶段治疗。研究 AD 的 NHP 模型，其中鞘内注射淀粉样蛋白 β-寡聚物 (AβOs) 诱导内侧颞皮质记忆回路中磷酸化 tau 蛋白的表达增加。与我们的总体假设一致，即 AβO 会引发一系列类似的加速病理学 AD 患者大脑中发生的变化这一假设是基于 AD 中日益增长的共识。 AβOs 是引起特征性缠结和斑块沉积的有毒物质的研究领域该假设将导致大脑中神经元和突触的丧失以及相关的认知能力下降。通过追求三个具体目标，在具有物理意义的设计中进行进一步测试：1）确定范围和诱发认知缺陷的持续性；2）使用药物干预，以及 3) 评估遥测植入物的脑电图记录在跟踪方面的效用正在进行的 AD 样病理学研究将利用生活中的生物标志物（MRI 确定的海马体积， CSF 分析物）以及死后测量（免疫组织化学、生物化学、电子显微镜）以确定 AβOs 给药对雄性和雌性圣基茨绿脑的影响猴子是一种因其倾向于发展自然发生的特征而被充分表征的物种该方法具有创新性，因为它代表了当前 AD 研究的重大转变。范式并测试了一个新颖的理论概念，这项研究意义重大，因为它预计：1）通过验证加速、诱导型 NHP 模型，克服当前动物 AD 模型的关键缺陷男性和女性中散发性 AD 的发病率，2) 允许将基本发现有效转化为新的临床诊断策略和治疗，3) 帮助了解疾病易感性中可能存在的性别差异该计划的成功将为需要的研究小组提供宝贵的资源。用于基础研究、诊断和治疗开发的相关、可靠的 AD 模型。