Alzheimer's Disease Pathology in a Primate Model

项目摘要 阿尔茨海默病(AD)是一种主要的健康问题，其定义是大脑的病理变化 与行为和认知功能的改变相吻合。动物模型提高了我们对AD的理解， 但这些模型人为地诱导神经病变来模拟人类疾病。例如，当淀粉样蛋白- β(Aβ)沉积在大多数哺乳动物中，tau阳性的神经原纤维缠结(NFT)只有 在迄今为止研究过的几个非人类物种中发现了这种病毒。我们的研究团队最近发现，黑猩猩， 我们最接近的基因亲戚之一，自然地同时患上Aβ斑块和神经纤维瘤，这是该病的病理特征 广告。除了AD的病理之外，老年黑猩猩还会患上脑淀粉样血管病(CAA)，即 80%的AD患者存在神经血管疾病，与认知能力下降有关。因此，额外的 对黑猩猩的研究可能会为AD和CAA的病因学提供新的线索，从而可能产生新的 治疗干预的指导。拟议研究的整体目标是进一步研究 黑猩猩衰老、CAA和AD的病理、表观遗传学和认知特征。在目标1中，我们将 进行全面的病理分析，以量化CAA和AD的生物标记物，包括Aβ40 和Aβ42斑块和血管体积、神经管密度、周细胞和血管体积、神经元和 突触密度和线粒体功能障碍。将对集体神经病理测量进行检查 在一个有生前认知数据的黑猩猩样本中，主要关注点是 确定哪些病理标记物最能预测认知的个体差异。此外，我们还将测试 AD和CAA病理与炎症过程的相关性，如小胶质细胞激活和 星形胶质细胞增多症。在目标2中，我们将量化黑猩猩种群的表观遗传年龄，并评估 与类人猿相比，患有CAA或AD损伤的黑猩猩表现出大脑表观遗传衰老的加速 没有病理改变。我们还将确定表观遗传年龄是否比实际年龄更好地预测 认知、特定区域灰质体积、白质完整性和连接性的变化。最后， 尽管之前的研究已经发现黑猩猩在认知方面的年龄差异，但我们将 确定黑猩猩是否表现出认知的纵向变化，以及是否有任何与年龄相关的丧失 在这项建议中，性能预测了AD病理的后续表达。所有生物材料和 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，在他们的 将填补我们对衰老和疾病的比较生物学知识的一个重要空白 并可能提供关键的翻译洞察，了解这些过程如何有助于 CAA和AD在人类中的进展。这些信息将为未来的翻译提供重要的方向 使用啮齿动物和非人灵长类动物模型进行的研究。

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.