Development of an Innovative Vervet (Chlorocebus aethiops sabaeus) Model of Early Alzheimer's-like Neuropathology and Symptomatology

本申请是对RFA-AG-21-003：阿尔茨海默病的新型/非常规动物模型的回应 （AD）。目前可用的AD动物模型主要模拟不太常见的早发性家族性AD， 在临床试验中的预测价值很低。然而，非人灵长类动物对于研究 迟发性散发性AD临床相关性越高，因为它们在脑中与人类的系统发育相似 结构和功能;复杂的内分泌，社会和认知特征;大尺寸有利于 影像学研究和脑脊液收集;以及tau和Aβ与人类的序列同源性 β-淀粉样蛋白（Aβ）。黑长尾猴表现出与人类相似的与年龄相关的大脑变化，包括Aβ斑块增加 负荷、认知和运动缺陷、脑脊液中AD生物标志物增加、成对螺旋丝tau蛋白 （PHF-tau）形成，脑容量减少，脑葡萄糖利用减少，皮质 转录谱NHP需要进一步研究，以了解其对发展中国家的明显抵抗力。 广泛的神经元缠结，这可能会提供洞察机制的基础弹性， 表征中枢神经系统tau蛋白种类，并开发Aβ和其他靶点的PET示踪剂 与AD和痴呆症相关。可改变的风险因素是早期干预的潜在目标， 人类的疾病包括肥胖、高血压、体力活动、葡萄糖耐量受损、心理社会压力和 可怜的睡眠。象人类一样对压力作出反应，并可能变得肥胖。年龄会增加他们的 高血压、糖耐量异常伴脑脊液Aβ42/Aβ40降低。 因此，黑长尾雉可能为与迟发性癫痫高度相关的转化和机制研究提供了机会。 零星AD。这项研究的前提是，长尾猴是一种很有前途的迟发性 散发性AD，其中AD相关疾病进展可通过早期干预表征和改变 可改变的风险因素。总体目标是进一步开发、表征和验证vervet 模型的神经病理学和认知能力下降，同时确定新的目标，为早期干预AD 特色我们的具体目标是确定认知和身体功能的年龄相关变化， 脑脊液和成像生物标志物;通过表征可改变的 迟发性散发性AD的风险因素;并评估这些风险因素对 来自我们的长尾猴研究群的30只长尾猴（从10岁到30岁）的神经病理学， 老龄Vervet队列。维克森林的独特资源将确保我们的目标快速进展，包括 我们的阿尔茨海默病研究中心;老龄化的Vervet队列，广泛的生物标本，数据和图像 存储库、独特的非人类灵长类动物成像能力、非人类灵长类动物研究的专业知识，以及 与我们的Claude D.佩珀老年美国人独立中心。

This application is in response to RFA-AG-21-003: New/Unconventional Animal Models of Alzheimer’s Disease (AD). Currently available animal models of AD mostly model the less common early-onset familial AD and have poor predictive value in clinical trials. However, nonhuman primates are useful for studying characteristics of the more clinically relevant late-onset sporadic AD because of their phylogenetic similarity to humans in brain structure and function; complex endocrine, social, and cognitive characteristics; large size favorable for imaging studies and cerebrospinal fluid collection; and sequence homology with humans for both tau and Aβ beta-amyloid (Aβ). Vervets show age-related brain changes similar to humans, including increased Aβ plaque burden, cognitive and motor deficits, increased AD biomarkers in cerebrospinal fluid, paired helical filament tau (PHF-tau) formation, decreased brain volumes, decreased cerebral glucose utilization, and altered cortical transcription profiles. NHPs require further study to understand their apparent resistance to developing extensive neurofibrillary tangles which may provide insight into mechanisms underlying resilience, to characterize central nervous system tau species, and to develop PET tracers for Aβ and other targets associated with AD and dementia .Modifiable risk factors that are potential targets for early intervention in humans include obesity, hypertension, physical activity, impaired glucose tolerance, psychosocial stress, and poor sleep. Vervets respond to stress like humans and may become obese. Age increases their rates of hypertension and impaired glucose tolerance accompanied by decreased Aβ42/Aβ40 in cerebrospinal fluid. Thus, vervets may provide opportunities for translational and mechanistic research highly relevant to late-onset sporadic AD. The premise of the proposed research is that vervets are a promising model of late-onset sporadic AD in which AD-related disease progression could be characterized and altered by early intervention on modifiable risk factors. The overarching goal is to further develop, characterize, and validate the vervet model of neuropathology and cognitive decline, while identifying novel targets for early intervention for AD characteristics. Our Specific Aims are to determine age-related changes in cognitive and physical function, cerebrospinal fluid and imaging biomarkers; identify targets for early intervention by characterizing modifiable risk factors for late-onset sporadic AD; and assess the predictive validity of these risk factors for neuropathology in 30 vervets from our Vervet Research Colony (from 10 to 30 years old) which comprise the Aging Vervet Cohort. Unique resources at Wake Forest that will assure rapid progress toward our goal include our Alzheimer’s Disease Research Center; Aging Vervet Cohort, extensive Biospecimen, Data and Image Repository, unique nonhuman primate imaging capabilities, expertise in nonhuman primate research, and close collaboration with our Claude D. Pepper Older Americans Independence Center.