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.

该应用是对RFA-AG-21-003：阿尔茨海默病的新/非常规动物模型的响应 (Ad)。目前可用的AD动物模型大多是较不常见的早发性家族性AD模型，并有 在临床试验中预测价值较差。然而，非人灵长类动物对研究人类的特征是有用的 临床上更相关的迟发性散发性阿尔茨海默病，因为他们与人类在大脑中的系统发育相似 结构和功能；复杂的内分泌、社会和认知特征；大尺寸有利于 成像研究和脑脊液收集；tau和Aβ与人类的序列同源性 β-淀粉样蛋白(Aβ)。Vervets显示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、认知和运动障碍、脑脊液中AD生物标志物增加、成对的螺旋微丝tau (PHF-tau)形成，脑体积减少，大脑葡萄糖利用率降低，皮质改变 转录档案。NHP需要进一步研究才能了解它们对发展的明显阻力 广泛的神经原纤维缠结，可能提供对潜在弹性的机制的洞察， 确定中枢神经系统tau的种类，并开发针对Aβ和其他靶点的正电子发射计算机断层扫描示踪剂 与阿尔茨海默病和痴呆相关。可调整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、心理社会压力以及 睡眠不佳。马鞭草像人类一样对压力做出反应，可能会变得肥胖。年龄增加了他们的发病率 高血压和糖耐量减低伴有脑脊液Aβ42/Aβ40降低。 因此，马鞭草可能会为与迟发性疾病高度相关的翻译和机械研究提供机会。 零星的AD。拟议研究的前提是马鞭草是一种很有前途的迟发性模型。 可以通过早期干预来表征和改变AD相关疾病进展的散发性AD 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vervet 神经病理和认知功能下降的模型，同时确定AD早期干预的新靶点 特点。我们的具体目标是确定与年龄相关的认知和身体功能的变化， 脑脊液和成像生物标志物.通过表征可修改的特征来识别早期干预的靶点 迟发性散发性AD的危险因素；评估这些危险因素对 来自我们的Verveet Research Colony(10-30岁)的30只脊椎动物的神经病理学研究 年迈的韦尔维队列。维克森林的独特资源将确保我们实现目标的快速进展，包括 我们的阿尔茨海默病研究中心；老年韦韦特队列，广泛的生物显微镜，数据和图像 存储库，独特的非人灵长类成像能力，非人灵长类研究的专业知识，以及 与克劳德·D·佩珀老年美国人独立中心密切合作。