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

淀粉样β寡聚体在非人灵长类动物中诱导阿尔茨海默氏病

• 批准号: 9765816
• 负责人: Dustin Robert Wakeman
• 金额: $ 4.9万
• 依托单位: VIRSCIO, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2019-03-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765816
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; American; Animal Model; Animals; Appearance; Autopsy; Back; Basic Science; Biochemical; Biochemistry; Biodistribution; Biological Markers; Biotechnology; Brain; Cercopithecus pygerythrus; Cessation of life; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Consensus; Data; Dependence; Deposition; Development; Diagnostic; Diffusion; Disease; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Early Diagnosis; Endocrinology; Evaluation; Failure; Family Caregiver; Fostering; Functional disorder; Future; Gene Mutation; Genetic; Genomics; Goals; Healthcare Systems; Heart Diseases; Hippocampus (Brain); Histologic; Human; Immunohistochemistry; Immunology; Impaired cognition; Impairment; Incidence; Industry; Infusion procedures; Injections; Institutes; Intervention; Intrathecal Injections; Laboratories; Lead; Life; Longevity; Magnetic Resonance Imaging; Measurement; Measures; Memory; Memory Loss; Mission; Modeling; Monkeys; Mortality Decline; 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; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Outcome Study; Pathologic; Pathology; Patients; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Physiology; Play; Pre-Clinical Model; Preclinical Testing; Prefrontal Cortex; Prevalence; Program Development; Public Health; Rare Diseases; Rattus; Regimen; Reproducibility; Research; Resources; Risk; Risk Factors; Rodent; Role; Senile Plaques; Standardization; Symptoms; Synapses; System; Testing; Time; Tissues; Translating; Translations; Treatment Efficacy; United States National Institutes of Health; Work; abeta oligomer; base; clinical diagnostics; clinical efficacy; cognitive ability; cognitive testing; combat; cost effective; design; disability; effective therapy; familial Alzheimer disease; gray matter; health economics; human model; in vivo; innovation; model development; mouse model; nonhuman primate; novel; novel diagnostics; novel strategies; novel therapeutics; preclinical study; prevent; social; success; symptom treatment; tau aggregation; therapeutic development; treatment strategy

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.

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。目前，有11％的美国人有65岁以上的AD及其事件，并且 医疗体系的损失会随着重大的社会影响而继续增长。没有广告的治疗方法 为了防止其不可驱动的过程，以及开发广告新疗法的主要障碍一直是 可用的临床前建模不足，几乎完全涉及啮齿动物。作为非人类 在各个方面，素数（NHP）与啮齿动物具有更大的同源性，包括基因组学和 生理学，认知处理，神经元网络复杂性，白色/灰质比，动力学 药物/靶标相互作用以及与年龄相关的病理生理学的触发器，这是该项目的长期目标 是为了开发一种可以标准化和部署在严格，可重复的研究中的新的NHP AD模型 在将临床前研究转化为新型临床诊断策略时，要克服关键的当前缺陷 和疗法。该应用程序的目的是扩展和推进最新的初步工作 NHP的AD模型，涉及黑过淀粉样蛋白β-橄榄剂（AβOS）的AD模型。假设是 AβOS将触发一系列加速病理，该病理模仿AD大脑中发生的变化 患者。该假设基于在广告研究领域的共识越来越大，并以强大的数据支持， AβOS可能是引起特征缠结和斑块沉积的有毒物种 大脑以及突触和神经元的丧失以及相关的认知下降。假设将是 通过追求以下两个具体目的在统计上有意义的设计中测试：1）确定 适当剂量的AβO和给药间隔； 2）确定诱导的生化和 终止AβO输注后，结构定义了AD病理。这些研究将利用生命（MRI） 和验尸测量（免疫组织化学，生物化学）以建立AβOS的影响 在圣基茨绿猴的大脑中的管理，该物种的特征是 发展AD病理的自然特征的倾向。这种方法是创新的，因为它 与当前的AD研究范式相去甚远，并测试了一种新颖的理论概念。这 研究之所以重要，是因为有望通过 验证零星AD的加速，可诱导的NHP模型，并允许基础研究的有效翻译 进入新型的临床诊断策略和疗法。通过此模型开发计划的成功将 为需要的学术，生物技术，药物和诊断实验室提供宝贵的资源 用于基础研究以及诊断和治疗发展的AD的可靠临床前模型。