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.

项目摘要 阿尔茨海默氏病（AD）是大脑病理变化所定义的主要健康问题， 与行为和认知功能的改变相吻合。动物模型提高了我们对广告的理解， 但是这些模型人为地诱导神经病来模拟人类疾病。例如，淀粉样蛋白 β（Aβ）沉积发生在大多数哺乳动物中，tau阳性神经纤维缠结（NFT）仅是 在迄今为止研究的一些非人类物种中鉴定出来。我们的研究小组最近发现黑猩猩， 我们的壁橱遗传亲戚之一，自然发展了Aβ斑块和NFT，即病理标志 广告。除了AD病理外，较早的黑猩猩还会发展出脑淀粉样血管病（CAA），A 在80％的AD患者中，与认知能力下降有关的AD患者中发现了神经血管疾病。因此，其他 黑猩猩的研究可能会对AD和CAA的病因进行新的启示，从而导致潜在的新 治疗干预的方向。拟议研究的总体目标是进一步研究 在AIM 1中，我们将 进行旨在量化CAA和AD的生物标志物的综合病理分析，包括Aβ40 以及Aβ42斑块和容器体积，NFT密度，周细胞和平滑肌细胞容器，神经元和 突触密度和线粒体功能障碍。将检查集体神经病理学措施 在有抗虫认知数据的黑猩猩样本中，主要重点将是 确定哪种病理标记最能预测认知的个体变异。而且，我们将测试 AD和CAA病理与炎症过程的相关性，例如小胶质激活和 星形胶质病。在AIM 2中，我们将量化黑猩猩种群中的表观遗传年龄，并评估是否是否 具有CAA或AD病变的黑猩猩表现出相对于猿的加速性表观遗传衰老 没有病理。我们还将确定表观遗传年龄是否比年龄更好 认知，特定区域的灰质体积以及白质完整性和连通性的变化。最后， 尽管以前的研究发现黑猩猩认知的横截面年龄差异，但我们将 确定黑猩猩是否显示认知的纵向变化以及是否有任何与年龄相关的损失 绩效预测该提案中AD病理的随后表达。所有生物材料和 在拟议的研究中获得的认知数据将添加到国家黑猩猩大脑资源和 通过网络门户向科学界公开提供。提出的研究， 个人，将填补我们关于衰老和疾病比较生物学的重要差距 黑猩猩，可能会提供有关这些过程如何促进这些过程的关键翻译见解 人类CAA和AD的进展。此信息将为将来的翻译提供至关重要的方向 使用啮齿动物和非人类灵长类动物模型的研究。