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.

项目摘要阿尔茨海默氏病（AD）患者的记忆力和认知能力逐渐逐渐丧失，最终基本身体功能和死亡的丧失。 AD在医疗保健系统上的事件和通行随着重大的社会影响而崛起。 AD没有治疗方法可以防止其不可阻止的过程，并且开发新疗法的主要障碍是可用临床前的不足建模，几乎完全涉及啮齿动物。非人类灵长类动物（NHP）与人类在所有方面都比啮齿动物，包括基因组学，生理学，认知处理，神经元网络药物/目标相互作用的复杂性和动力学。鉴于这些翻译优势，长期目标该项目的是开发一种新的NHP AD模型，可以标准化和以严格的，严格的方式部署可再现的研究，以克服将临床前研究转化为新临床的关键当前缺陷诊断策略和疗法。该应用的目的是扩展和推进我们的第一阶段在AD的NHP模型上工作，其中鞘内施用淀粉样β-溶藻（AβOS）会诱导磷酸化tau表达增加在中值临时皮质记忆回路中。这个发现是与我们的总体假设一致，即AβOS将触发一系列加速病理，模仿 AD患者的大脑发生的变化。该假设基于广告中日益增长的共识研究领域AβOS是引起特征缠结和斑块沉积的有毒物种在大脑中，以及神经元和突触的丧失以及相关的认知下降。该假设将通过追求三个具体目的，在统计上有意义的设计中进一步测试：1）确定程度和诱发认知缺陷的持久性； 2）使用A确认模型的预测有效性药理学干预和3）评估遥测直接的脑电图记录的效用正在进行的类似广告的病理学。这些研究将利用生命生物标志物（MRI确定的海马体积， CSF分析）以及验尸测量（免疫组织化学，生物化学，电子化学显微镜），以建立AβOS给药在男性和女性圣基茨绿色的大脑中的影响猴子，该物种因其发展自然发生特征的承诺而被很好地特征广告病理学。这种方法具有创新性，因为它与当前的广告研究相比有很大的转变范式和测试一个新颖的理论概念。这项研究很重要，因为预计会1）通过验证加速的，可诱导的NHP模型来克服当前动物AD模型中的关键缺陷男性和女性的零星广告，2）允许将基本发现的有效翻译成新的临床诊断策略和疗法，以及3）有助于理解疾病易感性的性别差异和进展。该计划的成功将为需要一个的研究小组提供宝贵的资源相关的，可靠的AD模型，用于基础研究以及诊断和治疗开发。