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

衰老、CAA 和阿尔茨海默病中的蛛网膜颗粒衰老

• 批准号: 10525081
• 负责人: Rupal I. Mehta
• 金额: $ 43.45万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10525081
• 关键词: Age; Aging; Alpha Granule; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anatomy; Apolipoprotein E; Arachnoid mater; Area; Brain; Cells; Cerebral Amyloid Angiopathy; Cerebral small vessel disease; Cerebrospinal Fluid; Clinical; Cognition; Collaborations; Communities; Cytoplasmic Granules; Data; Dementia; Diagnosis; Diagnostic; Diagnostic Factor; Disease; Epidemiology; Future; Genotype; Histology; Homeostasis; Human; Human Characteristics; Impaired cognition; Individual; Investigation; Knowledge; Lead; Liquid substance; Lymphatic; Lymphatic clearance; Maps; Measures; Memory; Meningeal; Meningeal lymphatic system; Microscopic; Microscopy; Morphology; Movement; Nature; Nerve Degeneration; Nervous system structure; Neuroanatomy; Neuroimmune; Neurologic; Pathologic; Persons; Physiology; Play; Prognostic Factor; Research; Resolution; Resources; Role; Sampling; Severities; Stroke; Structure; Techniques; Therapeutic; Tissues; Universities; Work; abeta accumulation; age related; apolipoprotein E-4; cohort; comorbidity; glymphatic clearance; glymphatic system; insight; lymphatic drainage; macrophage; member; monocyte; nervous system disorder; neuropathology; neurovascular; novel; prognostic; protein aggregation; proteostasis; religious order study; resilience; response; secondary analysis; senescence; sex; wasting

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.

项目概要/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， 已知会随着年龄的增长而增大。越来越多的证据表明 AG 在类淋巴系统中发挥特殊作用 淋巴引流，可能是大脑恢复能力和疾病（包括阿尔茨海默病）的关键因素。 尽管如此，这些脑膜结构在不同物种之间的研究还很有限。从历史上看，AG 被认为在颅内脑脊液运输中发挥被动作用。知识上的巨大差距 仍然关于它们的细胞成分和排列，以及它们与疾病的关联，这在很大程度上是由于 缺乏系统和高分辨率的微观分析。为了推进该领域的发展，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其结构 人类 AG 及其形态和成分随衰老的变化。他们的解剖结构将被绘制出来 使用免疫组织化学技术，其特征将与已建立的神经病理学相关 和疾病的神经学测量。对于这项工作，我们将利用丰富的临床和病理资源 材料可从 Rush Religious Orders Study 和 Memory and Aging Project (ROSMAP) 获得，并将 收集和分析与 AG 独特结构相关的新数据。假设 AG 的功能是 一种重要的神经免疫组织，其衰老与阿尔茨海默氏病（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 的关联 失智。在目标 3 中，我们将探讨载脂蛋白 E 基因型对 AG 之间关联的作用 颅内βA负荷和认知的衰老特征。在每个目标中，我们将研究关系如何 因年龄、临床或病理 AD 分期、性别和合并症而异。总体而言，这些研究有 揭示有关老龄化和 AD 中 AG 环境的新知识以及对衰老和 AD 的新见解的潜力 类淋巴连接的个体特异性。拟议的调查将推动 领域，并可能揭示 AD 的机制、诊断和预后因素，同时奠定研究框架 AG 用于治疗其他与年龄相关的神经系统疾病。

项目成果

The Vascular-Immune Hypothesis of Alzheimer's Disease.

• DOI: 10.3390/biomedicines11020408
• 发表时间: 2023-01-30
• 期刊: BIOMEDICINES
• 影响因子: 4.7
• 作者: Mehta, Rashi I.;Mehta, Rupal I.
• 通讯作者: Mehta, Rupal I.

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma.

• DOI: 10.1084/jem.20220618
• 发表时间: 2023-02-06
• 期刊: The Journal of experimental medicine
• 作者: Shah T;Leurgans SE;Mehta RI;Yang J;Galloway CA;de Mesy Bentley KL;Schneider JA;Mehta RI
• 通讯作者: Mehta RI

Giant Arachnoid Granulations: Diagnostic Workup and Characterization in Three Symptomatic Adults.

• DOI: 10.3390/ijms241411410
• 发表时间: 2023-07-13
• 期刊: International journal of molecular sciences
• 影响因子: 5.6