Tau based Monkey model of Alzheimer's Disease; Structure and Function

基于 Tau 的阿尔茨海默病猴子模型；

• 批准号: 10475169
• 负责人: Mark G Baxter
• 金额: $ 129.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475169
• 关键词: 13 year old; Adult; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Animals; Autopsy; Behavior; Behavior assessment; Bilateral; Biological Markers; Brain; Cognition; Cognitive; Data; Data Set; Dementia; Dependovirus; Development; Disease; Distal; Dose; Emotional; Emotions; Face; Future; Genetic; Goals; Health; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; Inflammation; Infusion procedures; Injections; Liquid substance; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Medial; Memory; Microscopic; Modeling; Monkeys; Nature; Nerve Degeneration; Neurofibrillary Tangles; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Phase; Phylogeny; Physiology; Plasma; Positron-Emission Tomography; Process; Request for Proposals; Rodent; Sampling; Serum; Site; Social Behavior; Structure; Synapses; Tauopathies; Temporal Lobe; Testing; Therapeutic Agents; Time; Translating; Validation; Viral; Work; base; behavioral impairment; behavioral study; cognitive task; cognitive testing; cost; design; effective therapy; entorhinal cortex; experience; hippocampal atrophy; imaging study; improved; in vivo; in vivo imaging; memory recognition; neocortical; neuroinflammation; neuron loss; neuropathology; neuroprotection; nonhuman primate; novel therapeutics; object recognition; prevent; programs; tau Proteins; tau aggregation; tau expression; tau mutation; tau-1; therapeutic development; therapeutic evaluation; therapy design; translational model; translational potential; vector

Alzheimer’s disease (AD) is a devastating condition that affects more than 5 million Americans, with a total annual cost of more than $300 billion predicted in 2020. Currently there are no effective treatments to counteract or slow the progression of AD, with promising findings in rodents failing to translate into successful therapies for patients. Monkey models may provide a more powerful translational model. The goal of this proposal is to characterize a monkey model of tau pathology in AD. This is responsive to RFA-AG-21-003 requesting proposals that target the “development, characterization, and validation of suitable new or unconventional mammalian non-murine models of AD that may represent improved translational potential by better replicating pathological features of the disease”. With respect to nonhuman primate (NHP) models of AD, the RFA states explicitly that “NHP have a very high translational value because of their close relationship to humans in terms of phylogeny, genetics, physiology, cognition, emotion, and social behavior”. In this proposal we describe initial findings in a tau-based monkey model of AD and propose a program to fully develop and validate the model by three PIs who have decades of experience on aging and neurodegeneration in NHP models. We have targeted the highly vulnerable entorhinal cortex (ERC) for unilateral infusions of an adeno-associated virus expressing a double tau mutation known to cause tau-related dementia in humans (AAV-P301L/S320F) and characterized neuropathology at 3 and 6 months after viral injection in NHPs. This causes extensive and progressive neuroinflammation and tau-based neuropathology, including end-stage neurofibrillary tangles, in ERC and in hippocampal and neocortical targets of ERC. Preliminary PET imaging in these monkeys displays robust phospho-tau accumulation in the hippocampus. The progressive time course relative to the time of vector injection is a great strength in terms of using this model for therapeutic development. These early studies demonstrate the potential for this model to replicate pathological features of AD in the monkey brain and to capture aspects of pathology that have not been well-modeled in rodents. We propose to do a full, rigorous characterization of this model, including long-term behavioral assessment, in vivo imaging, fluid biomarker assessment, and microscopic analyses. Full characterization of this model, will provide a platform to test therapeutic agents at different points in the disease process.

阿尔茨海默氏病（AD）是一种毁灭性的疾病，影响了超过500万美国人， 预计2020年的年度总成本超过3000亿美元。目前尚无效果 治疗以抵消或减慢AD的进展，并承诺在啮齿动物中发现 转化为患者的成功疗法。猴子模型可能会提供更强大的 翻译模型。该建议的目的是表征tau病理学的猴子模型 在广告中。这对RFA-AG-21-003的响应敏感，要求针对“开发， 表征和验证合适的新型或非常规哺乳动物非乳腺模型 通过更好地复制病理学来代表改进的翻译潜力的AD RFA状态 明确地说：“ NHP具有很高的翻译价值，因为它们与 人类在系统发育，遗传学，生理，认知，情感和社会行为方面”。 该提案我们在基于tau的AD和提案的猴子模型中描述了初步发现。 通过三个有数十年经验的PI进行充分开发和验证模型的计划 NHP模型中的衰老和神经变性。我们针对高度脆弱的内河 与表达双tau的腺相关病毒单侧输注的皮层（ERC） 已知会导致人类中与tau相关的痴呆的突变（AAV-P301L/s320f）并表征 NHP病毒注射后3和6个月的神经病理学。这会导致广泛的 进行性神经炎症和基于TAU的神经病理学，包括终末期神经纤维 缠结，在ERC和ERC的海马和新皮层靶标中。初步的宠物成像 这些猴子在海马中显示出强大的磷酸-TAU积累。进步 相对于矢量注入时间的时间课程在使用此模型方面是一个很大的优势 用于治疗发展。这些早期研究表明了该模型的潜力 复制AD在猴子大脑中的病理特征，并捕获病理的方面 在啮齿动物中尚未进行良好的模型。我们建议对此做一个完整，严格的特征 模型，包括长期行为评估，体内成像，流体生物标志物评估， 和显微镜分析。该模型的全面表征将提供一个测试平台 疾病过程中不同点的治疗剂。