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

阿尔茨海默病(AD)是一种毁灭性的疾病，影响着500多万美国人， 预计2020年的年总成本将超过3000亿美元。目前还没有有效的 对抗或减缓阿尔茨海默病进展的治疗方法，在啮齿动物身上取得了令人振奋的发现 为患者提供成功的治疗方法。猴子模型可能会提供更强大的 翻译模型。这项提议的目标是描述一种tau病理的猴子模型。 在公元后。这是对RFA-AG-21-003号文件的响应，该文件请求针对“发展， 合适的新的或非传统的哺乳动物非小鼠模型的表征和验证 这可能代表了通过更好地复制病理组织来提高翻译潜力 疾病的特点“。关于AD的非人灵长类(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 人类在进化史、遗传学、生理学、认知、情感和社会行为方面的差异“。在……里面 这项建议我们描述了基于tau的阿尔茨海默病猴子模型的初步发现，并提出了一种 由三名具有数十年经验的PI全面开发和验证模型的计划 NHP模型的衰老和神经退行性变。我们已经锁定了高度脆弱的内脏 皮层(ERC)用于单侧输注表达双tau的腺相关病毒 已知导致人类tau相关性痴呆的突变(AAV-P301L/S320F) NHP患者注射病毒后3个月和6个月的神经病理改变。这导致了广泛和 进行性神经炎和基于tau的神经病理，包括终末期神经原纤维 在ERC和ERC的海马区和新皮质靶区。初步的正电子发射断层扫描 这些猴子在海马体中表现出强大的磷酸-tau积累。进步者 相对于载体注射时间的时间进程是使用该模型的一个很大的优势 用于治疗发展。这些早期的研究证明了这种模式的潜力 复制猴子大脑中阿尔茨海默病的病理特征，并捕获 在啮齿动物身上还没有很好的模型。我们建议对此做一个全面、严谨的描述 模型，包括长期行为评估、活体成像、流体生物标记物评估、 和显微分析。该模型的充分表征，将为测试提供一个平台 治疗药物在疾病过程中的不同阶段。

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.