Arachnoid Granulation Senescence in Aging, CAA and Alzheimer's Disease

项目总结/摘要 蛛网膜颗粒（AG）是哺乳动物神经系统内独特的组织复合物， 随着年龄的增长而增大。越来越多的证据表明，AGs在胶质淋巴细胞中起着特殊的作用。 淋巴引流，可能是大脑恢复力和疾病的关键因素，包括阿尔茨海默病。 尽管如此，这些脑膜结构在不同物种中的研究很少。从历史上看， 被认为在颅内脑脊液运输中起被动作用。知识方面的巨大差距 关于它们的细胞成分和排列，以及它们与疾病的关系，在很大程度上是由于 缺乏系统和高分辨率的显微分析。为了推进该领域，更好地表征 需要AG结构。在这项研究中，我们将使用高分辨率显微镜技术来阐明结构 人AG及其形态和成分随年龄的变化。他们的解剖结构将被绘制在 使用免疫组织化学技术，其特征将与已建立的神经病理学 和神经系统疾病的测量。为了这项工作，我们将利用丰富的临床和病理资源， 材料可从拉什宗教秩序研究和记忆和老龄化项目（ROSMAP），并将 收集和分析与AG的独特结构有关的新数据。假设AG的功能是 一种重要的神经免疫组织，它们的衰老与阿尔茨海默病（AD）有关。在目标1中， 我们将研究AG衰老与颅内β-淀粉样蛋白（βA）积累的关系， AD的病理学在目标2中，我们将研究AG衰老与临床定义的AD之间的关系 痴呆在目的3中，我们将探讨载脂蛋白E基因型在AG之间的关联中的作用， 脑内βA负荷和认知功能的衰老特征。在每一个目标中，我们将研究关系如何 不同的年龄，临床或病理AD阶段，性别和共病疾病。总的来说，这些研究 潜在的发现新知识的AG环境在老化和AD，以及新的见解， 淋巴管-淋巴管连接的个人特异性。拟议的调查将推动 这一领域的研究，可能揭示AD的机制，诊断和预后因素，同时为研究奠定框架 AGs在其他年龄相关神经系统疾病中的应用。

PROJECT SUMMARY/ABSTRACT Arachnoid granulations (AG) are a unique tissue composite within the mammalian nervous system and are known to enlarge with aging. Accumulating evidence suggest that AGs subserve specialized roles in glymphatic- lymphatic drainage and may be a critical factor in brain resilience and diseases, including Alzheimer’s disease. In spite of this, these meningeal structures have been poorly investigated across species. Historically, AGs have been perceived to play a passive role in intracranial cerebrospinal fluid transport. Substantial gaps in knowledge remain regarding their cell constituents and arrangement, and their associations with disease, due in large part to lack of systematic and high-resolution microscopic analyses. To advance the field, better characterization of AG structure is needed. In this study, we will use high-resolution microscopy techniques to elucidate the structure of human AG and their morphological and compositional changes with aging. Their anatomy will be mapped using immunohistochemical techniques and their features will be correlated with established neuropathological and neurological measures of disease. For this work, we will leverage a rich resource of clinical and pathologic material available from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) and will collect and analyze novel data pertaining to the unique structure of AG. The hypothesis is that AGs function as a critical neuroimmune tissue and that their senescence is associated with Alzheimer’s disease (AD). In Aim 1, we will examine the associations of AG senescence with intracranial beta-amyloid (βA) accumulation and pathology of AD. In Aim 2, we will examine the associations of AG senescence with clinically defined AD dementia. In Aim 3, we will explore the role of apolipoprotein E genotype on the associations between AG senescent features with intracranial βA load and cognition. In each aim, we will investigate how relationships differ by age, clinical or pathological AD stage, sex, and comorbid diseases. Overall, these studies have the potential to uncover new knowledge regarding the AG milieu in aging and AD as well as novel insights into the person-specific nature of the glymphatic-lymphatic connection. The proposed investigations will advance the field and may reveal mechanistic, diagnostic and prognostic factors for AD while laying a framework for studying AGs in the setting of other age-related neurological diseases.