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: 10281758
• 负责人: SUZANNE CRAFT
• 金额: $ 131.15万
• 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/10281758
• 关键词: Achievement; 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; 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; Neuraxis; Neurocognitive Deficit; Neurofibrillary Tangles; Obesity; Outcome; Peptides; 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; Tissue imaging; Tracer; Transgenic Mice; Transgenic Model; Translating; age related; 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; 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.

此应用程序是为了响应 RFA-AG-21-003：阿尔茨海默病的新/非常规动物模型 （广告）。目前可用的 AD 动物模型大多模拟不太常见的早发性家族性 AD，并且具有 临床试验中的预测价值较差。然而，非人类灵长类动物可用于研究 晚发散发性AD在临床上更具相关性，因为它们与人类大脑的系统发育相似 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采集； tau 和 Aβ 与人类的序列同源性 β-淀粉样蛋白（Aβ）。黑长尾黑颚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 负担、认知和运动缺陷、脑脊液中 AD 生物标志物增加、配对螺旋丝 tau (PHF-tau) 形成、脑容量减少、大脑葡萄糖利用率降低以及皮质改变 转录概况。 NHP 需要进一步研究以了解其对发展的明显阻力 广泛的神经原纤维缠结可以提供对弹性潜在机制的深入了解， 表征中枢神经系统 tau 蛋白种类，并开发 Aβ 和其他靶标的 PET 示踪剂 与 AD 和痴呆症相关。可改变的危险因素是早期干预的潜在目标 人类包括肥胖、高血压、体力活动、糖耐量受损、社会心理压力和 睡眠不好。黑长尾黑颚猴像人类一样对压力做出反应，并且可能会变得肥胖。年龄增加了他们的比率 高血压和糖耐量受损，伴有脑脊液中 Aβ42/Aβ40 减少。 因此，长尾黑颚猴可能为与晚发型发病高度相关的转化和机制研究提供机会 零星的AD。这项研究的前提是长尾黑颚猴是一种有前途的晚发模型 散发性 AD，其中与 AD 相关的疾病进展可以通过早期干预来表征和改变 关于可改变的风险因素。总体目标是进一步开发、表征和验证长尾黑颚猴 神经病理学和认知能力下降模型，同时确定 AD 早期干预的新目标 特征。我们的具体目标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；通过描述可修改的特征来确定早期干预的目标 晚发散发性 AD 的危险因素；并评估这些风险因素的预测有效性 对来自我们黑长尾猴研究群的 30 只黑长尾猴（10 至 30 岁）进行神经病理学研究，其中包括 老化长尾黑颚猴队列。维克森林大学的独特资源将确保我们的目标快速取得进展，包括 我们的阿尔茨海默病研究中心；老化长尾黑颚猴队列，广泛的生物样本、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方面的专业知识，以及 与我们的 Claude D. Pepper 美国老年人独立中心密切合作。