Alzheimer's Disease Pathology in a Primate Model

灵长类动物模型中的阿尔茨海默病病理学

• 批准号: 10350661
• 负责人: WILLIAM D HOPKINS
• 金额: $ 74.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350661
• 关键词: Acceleration; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Autopsy; Behavior; Behavioral; Biocompatible Materials; Biological; Biological Markers; Biology of Aging; Blood Vessels; Brain; Brain Diseases; Cell Death; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Chronology; Cognition; Cognitive; Cognitive deficits; Cohort Effect; Communities; Comparative Biology; Data; Dementia; Deposition; Deterioration; Disease; Elderly; Electron Microscopy; Epigenetic Process; Etiology; Exhibits; Future; Genetic; Genome; Goals; Health; Human; Impaired cognition; Individual; Inflammatory; Knowledge; LDL-Receptor Related Protein 1; Lesion; Light; Lipoprotein Receptor; Longevity; Mammals; Measures; Mediating; Memory; Memory impairment; Methylation; Mitochondria; Modeling; Motor Skills; Nerve Degeneration; Neurofibrillary Tangles; Neurologic; Neurons; Neuropathy; Pan Genus; Pathologic; Pathology; Pattern; Performance; Pericytes; Play; Pongidae; Population; Prefrontal Cortex; Primates; Process; Proteins; Public Health; Regression Analysis; Research; Resources; Rodent; Sampling; Senile Plaques; Series; Site; Smooth Muscle Myocytes; Synapses; Testing; Therapeutic Intervention; Time; Variant; abeta deposition; age difference; age related; aged; astrogliosis; base; behavior test; brain morphology; cognitive change; cognitive function; cognitive performance; cognitive testing; cohort; density; experience; gray matter; human disease; individual variation; insight; mitochondrial dysfunction; neuroinflammation; neuron loss; neuropathology; neurovascular; nonhuman primate; species difference; tau Proteins; tissue biomarkers; translational study; translational therapeutics; walking speed; web portal; white matter

Project Summary Alzheimer's disease (AD) is a major health concern defined by pathologic changes in the brain that coincide with altered behavior and cognitive function. Animal models have advanced our understanding of AD, but these models artificially induce neuropathy to simulate the human disease. For instance, while amyloid- beta (Aβ) deposition occurs in most mammals, tau-positive neurofibrillary tangles (NFT) have only been identified in a few nonhuman species studied to date. Our research team recently discovered that chimpanzees, one of our closest genetic relatives, naturally develop both Aβ plaques and NFT, the pathological hallmarks of AD. In addition to AD pathology, elderly chimpanzees also develop cerebral amyloid angiopathy (CAA), a neurovascular condition found in 80% of AD patients associated with cognitive decline. Therefore, additional studies in chimpanzees could shed new light on the etiology of AD and CAA, leading to potentially new directions for therapeutic interventions. The overall goals of the proposed studies are to further examine the pathologic, epigenetic, and cognitive characteristics of aging, CAA, and AD in chimpanzees. In Aim 1, we will perform comprehensive pathologic analyses aimed at quantifying biomarkers of CAA and AD, including Aβ40 and Aβ42 plaque and vessel volumes, NFT density, pericyte and smooth muscle cell vessel volumes, neuron and synapse densities, and mitochondrial dysfunction. The collective neuropathologic measures will be examined in a sample of chimpanzees for which antemortem cognitive data is available, and the main focus will be determining which pathologic markers best predict individual variation in cognition. Moreover, we will test the correlation of AD and CAA pathologies with inflammatory processes, such as microglial activation and astrogliosis. In Aim 2, we will quantify epigenetic age in the chimpanzee population and evaluate whether chimpanzees with CAA or AD lesions demonstrate accelerated epigenetic aging in the brain relative to apes without pathology. We also will determine if epigenetic age is a better predictor than chronological age of changes in cognition, region-specific gray matter volume, and white matter integrity and connectivity. Finally, though previous studies have found cross-sectional age differences in cognition in chimpanzees, we will determine whether chimpanzees show longitudinal changes in cognition and whether any age-related loss in performance predicts the subsequent expression of AD pathology in this proposal. All biomaterials and cognitive data obtained in the proposed studies will be added to the National Chimpanzee Brain Resource and made publicly available to the scientific community through a web portal. The proposed studies, in their entirety, will fill an important gap in our knowledge about the comparative biology of aging and disease in chimpanzees and may provide critical translational insight into how those processes contribute to the progression of CAA and AD in humans. This information will provide crucial direction for future translational studies using rodent and nonhuman primate models.

项目概要 阿尔茨海默病 (AD) 是一种主要的健康问题，其定义为大脑的病理变化， 与行为和认知功能改变相一致，动物模型增进了我们对 AD 的理解， 但这些模型人为地诱发神经病变来模拟人类疾病，例如淀粉样蛋白。 β (Aβ) 沉积发生在大多数哺乳动物中，tau 阳性神经原纤维缠结 (NFT) 仅在 我们的研究小组最近在一些非人类物种的研究中发现了黑猩猩， 我们最亲近的遗传亲属之一，自然会形成 Aβ 斑块和 NFT，这是 Aβ 斑块的病理标志 除了 AD 病理之外，老年黑猩猩还会出现脑淀粉样血管病 (CAA)，这是一种淀粉样血管病。 发现 80% 的 AD 患者的神经血管状况与认知能力下降有关。 对黑猩猩的研究可能为 AD 和 CAA 的病因学提供新的线索，从而带来潜在的新发现 拟议研究的总体目标是进一步检查治疗干预措施的方向。 在目标 1 中，我们将探讨黑猩猩衰老、CAA 和 AD 的病理、表观遗传和认知特征。 进行全面的病理分析，旨在量化 CAA 和 AD 的生物标志物，包括 Aβ40 和 Aβ42 斑块和血管体积、NFT 密度、周细胞和平滑肌细胞血管体积、神经元和 将检查突触密度和线粒体功能障碍。 在可获得生前认知数据的黑猩猩样本中，主要关注点是 确定哪些病理标记可以预测认知的最佳个体差异。此外，我们将测试 AD 和 CAA 病理与炎症过程的相关性，例如小胶质细胞激活和 在目标 2 中，我们将量化黑猩猩群体的表观遗传年龄并评估是否存在星形胶质细胞增生。 与猿类相比，患有 CAA 或 AD 病变的黑猩猩大脑中的表观遗传衰老速度加快 我们还将确定表观遗传年龄是否比实际年龄更好的预测因素。 认知、特定区域灰质体积以及白质完整性和连接性的变化。 尽管之前的研究发现黑猩猩的认知存在横截面年龄差异，但我们将 确定黑猩猩是否表现出认知的纵向变化以及是否存在与年龄相关的认知损失 性能预测了本提案中所有生物材料和 AD 病理学的后续表达。 在拟议的研究中获得的认知数据将被添加到国家黑猩猩大脑资源和 通过门户网站向科学界公开提供拟议的研究。 整体而言，将填补我们关于衰老和疾病的比较生物学知识的一个重要空白 黑猩猩，并可能提供关键的转化见解，了解这些过程如何促进 这些信息将为未来的转化提供重要方向。 使用啮齿动物和非人类灵长类动物模型进行研究。