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

开发早期阿尔茨海默病样神经病理学和症状学的创新黑长尾猴（Chlorocebus aethiops sabaeus）模型

• 批准号: 10663993
• 负责人: SUZANNE CRAFT
• 金额: $ 129.82万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663993
• 关键词: Achievement; Adult; Affect; African Green Monkey; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Biological Markers; Biological Specimen Banks; Blood; Blood Pressure; Brain; Capsicum; Central Nervous System; Cercopithecus tantalus; Cerebrospinal Fluid; Cerebrum; Characteristics; Clinical Trials; Cognitive; Cognitive aging; Cognitive deficits; Collaborations; Collection; Complex; Data; Dementia; Development; Disease; Disease Progression; Early Intervention; Early Onset Familial Alzheimer' s Disease; Endocrine; Environment; Etiology; FDA approved; Gene Expression Profile; Genes; Glucose; Glucose Intolerance; Goals; Human; Hypertension; Image; Impaired cognition; Incidence; Intervention; Late Onset Alzheimer Disease; Liquid substance; Magnetic Resonance Imaging; Microtubules; Modeling; Neurocognitive Deficit; Neurofibrillary Tangles; Obesity; Outcome; Persons; Phylogenetic Analysis; Physical Function; Physical activity; Positron-Emission Tomography; Predictive Value; Protocols documentation; Psychosocial Stress; Research; Resistance; Resources; Risk Factors; Senile Plaques; Sequence Homology; Sleep; Stress; Structure; Symptoms; Tracer; Transgenic Mice; Transgenic Model; Translating; abeta accumulation; age related; biomarker identification; brain tissue; brain volume; clinically relevant; cognitive function; cohort; data repository; forest; glucose metabolism; image archival system; imaging biomarker; imaging capabilities; imaging study; impaired glucose tolerance; innovation; insight; modifiable risk; motor deficit; neuropathology; nonhuman primate; novel; overexpression; poor sleep; repository; resilience; response; social; study characteristics; symptomatology; tau Proteins; tau aggregation; translational potential; vervet

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.

该应用是响应RFA-AG-21-003：阿尔茨海默氏病的新/非常规动物模型 （广告）。当前可用的AD动物模型主要是建模不太常见的早期发作的家族广告，并且具有 临床试验中的预测价值差。但是，非人类隐私对于研究的特征很有用 由于其系统发育与大脑中的人类的系统发育相似，因此临床上相关的后期发病越多。 结构和功能；复杂的内分泌，社会和认知特征；大尺寸有利于 成像研究和脑脊液收集；和与人类的序列同源性tau和Aβ β-淀粉样蛋白（Aβ）。天文显示与年龄相关的大脑变化类似于人类，包括增加的Aβ斑块 负担，认知和运动定义，增加了脑脊液中的AD生物标志物，配对螺旋丝Tau （PHF-TAU）形成，改善脑量，脑葡萄糖利用率减少并改变皮质 转录曲线。 NHP需要进一步研究才能了解他们对发展的明显抵抗力 广泛的神经原纤维缠结，可能会洞悉弹性的机制， 表征中枢神经系统tau物种，并为Aβ和其他靶标开发宠物示踪剂 与AD和痴呆症相关的。可约束的风险因素，这是早期干预的潜在目标 人类包括肥胖，高血压，体育锻炼，葡萄糖耐受性受损，社会心理压力和 睡眠不好。天文对人类的压力做出反应，可能会肥胖。年龄提高了他们的率 高血压和葡萄糖耐受性受损，伴有脑脊液中Aβ42/Aβ40降低。 这是，天线可以为转化和机械研究提供与迟到高度相关的转化和机械研究的机会 零星广告。拟议的研究的前提是，黄斑是迟到的有望模型 散发性广告可以通过早期干预来表征和改变与广告相关的疾病进展 关于可修改的危险因素。总体目标是进一步发展，表征和验证Vervet 神经病理学和认知能力下降的模型，同时确定了早期干预的新目标 特征。我们的具体目的是确定与年龄相关的认知和身体功能变化， 脑脊液和成像生物标志物；通过表征可修改来确定早期干预的目标 晚期零星广告的危险因素；并评估这些风险因素的预测有效性 我们的Vervet Research Colony（从10至30岁）中的30个角膜中的神经病理学 老化的vervet队列。 Wake Forest的独特资源将在我们的目标中迅速发展 我们的阿尔茨海默氏病研究中心；衰老的vervet队列，广泛的生物循环，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. Peper老年人独立中心密切合作。