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；

基本信息

批准号：
10682436
负责人：
Mark G Baxter
金额：
$ 129.57万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
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/10682436
关键词：
13 year old Adult Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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 Human Image Impaired cognition Impairment Inflammation Infusion procedures Injections Liquid substance Macaca mulatta Magnetic Resonance Imaging Measurement Medial Memory Microscopic Modeling Monkeys Nature Neocortex 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 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

项目摘要

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.

阿尔茨海默病 (AD) 是一种毁灭性的疾病，影响着超过 500 万美国人，预计到 2020 年，年度总成本将超过 3000 亿美元。目前尚无有效的对抗或减缓 AD 进展的治疗方法，在啮齿动物身上取得了有希望的结果，但失败了为患者转化为成功的疗法可能会提供更强大的猴子模型。该提案的目标是表征 tau 病理学的猴子模型。这是对 RFA-AG-21-003 要求的针对“发展、合适的新的或非常规的哺乳动物非鼠模型的表征和验证 AD 可能代表通过更好地复制病理学来提高转化潜力 RFA 指出，关于 AD 的非人类灵长类动物 (NHP) 模型明确指出“NHP 具有非常高的转化价值，因为它们与人类的系统发育、遗传学、生理学、认知、情感和社会行为”。在这个提案中，我们描述了基于 tau 的 AD 猴子模型的初步发现，并提出了一个由三位拥有数十年经验的 PI 全面开发和验证该模型的计划 NHP 模型中的衰老和神经退行性变是我们的目标。皮质 (ERC)，用于单侧输注表达双 tau 的腺相关病毒已知会导致人类 tau 相关痴呆的突变 (AAV-P301L/S320F)，并进行了表征 NHP 中病毒注射后 3 个月和 6 个月的神经病理学结果会导致广泛和严重的后果。进行性神经炎症和基于 tau 的神经病理学，包括终末期神经原纤维缠结、ERC 以及 ERC 的海马和新皮质目标中的初步 PET 成像。这些猴子的海马体中显示出大量的磷酸 tau 蛋白积累。相对于矢量注入时间的时间进程是使用该模型的一大优势这些早期研究证明了该模型的潜力。在猴脑中复制 AD 的病理特征，并捕捉病理学的各个方面我们尚未在啮齿类动物中建立良好的模型，对此进行全面、严格的表征。模型，包括长期行为评估、体内成像、液体生物标志物评估、和微观分析该模型，将提供一个测试平台。疾病过程中不同阶段的治疗药物。