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

阿尔茨海默病（AD）是一种影响超过500万美国人的毁灭性疾病， 预计到2020年，每年的总成本将超过3000亿美元。目前没有有效 治疗，以抵消或减缓AD的进展，与有希望的发现，在啮齿动物失败 转化为成功的治疗方法。猴子模型可以提供更强大的 平移模型该提案的目标是表征tau病理学的猴模型 在AD中。这是对RFA-AG-21 - 003的响应，要求针对"开发， 合适的新的或非常规的哺乳动物非鼠模型的表征和验证 可能代表通过更好地复制病理性 疾病的特征”。关于AD的非人灵长类动物（NHP）模型，RFA指出 明确地说，"NHP具有非常高的翻译价值，因为它们与 人类在遗传学、遗传学、生理学、认知、情感和社会行为方面的差异"。在 我们描述了在基于tau的AD猴模型中的初步发现，并提出了 该计划由三名在以下方面拥有数十年经验的PI全面开发和验证模型 NHP模型中的衰老和神经变性。我们的目标是高度脆弱的内嗅 用于单侧输注表达双tau蛋白的腺相关病毒的ERC 已知在人类中引起tau相关痴呆的突变（AAV-P301L/S320F），并表征 NHP中病毒注射后3个月和6个月的神经病理学。这导致了广泛的， 进行性神经炎症和基于tau的神经病理学，包括终末期神经病理学 缠结，在ERC和海马和ERC的新皮质靶。初步PET成像， 这些猴子在海马体中显示出强烈的磷酸化tau积累。逐步 相对于矢量注入时间的时间过程在使用该模型方面是一个很大的优势 用于治疗发展。这些早期的研究证明了这种模型的潜力， 在猴脑中复制AD的病理学特征，并捕获 在啮齿类动物中还没有很好的模型。我们建议对这一现象进行全面、严格的描述 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。对这一模型进行充分的表征，将提供一个测试平台 治疗药物在疾病过程中的不同点。

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.