Differential clearance of pyroglutamate abeta through arachnoid and meningeal lymphatics in Alzheimer Disease

阿尔茨海默病中焦谷氨酸 abeta 通过蛛网膜和脑膜淋巴管的差异清除

基本信息

批准号：
9802866
负责人：
Christopher G. Janson
金额：
$ 38.93万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9802866
关键词：
Abeta clearance Accounting Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model American Amyloid beta-Protein Anatomy Arachnoid Membrane Arachnoid mater Attention Attenuated Automobile Driving Biochemical Biological Assay Blood - brain barrier anatomy Blood Circulation Blood Vessels Brain Brain region Cells Cervical Cervical lymph node group Clinical Cognitive Communities Confocal Microscopy Data Dementia Development Diffusion Disease Disease Progression Drainage procedure Dura Mater Electron Microscopy Endocytosis Endothelium Etiology Excision Failure Gold Growth Head and neck structure Human Image Immune Impaired cognition Impairment Label Lead Length Ligation Link Liquid substance Lymphatic Lymphatic Capillaries Lymphatic System Lymphatic vessel Maintenance Maps Measurement Membrane Meningeal Meninges Methods Mitochondria Modeling Molecular Mosaicism Mus Neurons Normal Cell Pathologic Pathway interactions Patients Peptides Pharmacology Play Post-Translational Protein Processing Proteins Proteomics Protocols documentation Pyroglutamate Rattus Research Research Personnel Resolution Rodent Model Role Route Structure System Testing Therapeutic Time Tissues Translating Viral Vector age effect age related base brain health clinically relevant exhaustion health management healthy aging human subject in vivo lymphatic drainage molecular diagnostics neurotoxic neurovascular novel prevent protein biomarkers sex solute targeted treatment three dimensional cell culture tissue processing tool uptake vascular risk factor wasting

项目摘要

Alzheimer's disease is a condition in which brain clearance of toxic peptides such as amyloid beta (Aβ) is impaired. Determining the mechanisms by which brain clearance becomes compromised will open up therapeutic opportunities for attenuating or preventing Alzheimer's disease. The field has focused much of its attention on vascular risk factors such as Aβ transport at the blood-brain barrier. Despite significant progress, the overarching problem of impaired Aβ brain clearance has not been solved. Thus, there is a need to consider alternative routes or mechanisms of clearance. The recently discovered meningeal lymphatic system is a prime candidate for the missing link between impaired Aβ clearance and Alzheimer's disease. This previously unrecognized network of intracranial drainage vessels is located in the meninges, or membranes surrounding the brain, and along with arachnoid membranes it actively participates in clearance of fluid and solutes from the brain. For many years, it was known that substances injected into the brain make their way to the lymphatic drainage system in the head and neck, but anatomical connections largely remained a "black box." Before the discovery of Aβ, researchers also found that ligation of cervical lymphatics resulted in cognitive impairment. However, a direct link between lymphatic drainage and dementia was never established. Correlative data now suggest that the meninges are involved in maintenance of brain health by managing the removal of endogenous waste to the systemic circulation. Yet there has been no clear functional link between meningeal lymphatics and major pathological features of Alzheimer's disease, and it is furthermore unclear how lymphatic function would become compromised during disease initiation or progression. Our hypothesis is that the meninges play a necessary and specific role in clearing neurotoxic pyroglutamate-Aβ (pE3-Aβ) and other Aβ species from the brain. We propose that pathological changes in lymphatic vessels and arachnoid membranes occur during aging, thereby promoting initiation or progression of Alzheimer's disease. To test this hypothesis, we have adapted the TgF344-AD rat model that carries key hallmarks of Alzheimer's disease. This was cross-bred with a rat expressing a fluorescent marker protein, so that lymphatic vessels are visualized in exquisite detail. In parallel, we are systematically examining human meninges in Alzheimer's disease. Aim #1 will examine energy-dependent mechanisms underlying lymphatic clearance, to provide new potential targets for drug therapy. Aim #2 will confirm anatomical correlates of the lymphatic system in aging and will modulate its function to prove causality and plasticity of the meningeal system. Aim #3 will establish the relevance of meningeal clearance of pE3-Aβ and Aβ to human Alzheimer's disease by creating a high resolution map of the human meninges and using proteomics and biochemical analysis to model clearance pathways. These studies will provide invaluable new tools for the research community and will enable therapeutic discovery.

阿尔茨海默病是一种大脑无法清除有毒肽（如β淀粉样蛋白 (Aβ)）的疾病。确定大脑清除受损的机制将会开放。该领域集中了许多减轻或预防阿尔茨海默病的治疗机会。尽管显着，但它仍关注血管危险因素，例如 Aβ 在血脑屏障的转运。然而，Aβ 大脑清除受损的首要问题尚未得到解决。需要考虑最近发现的脑膜清除的替代途径或机制。淋巴系统是 Aβ 清除受损与阿尔茨海默病之间缺失联系的主要候选者这种以前未被认识的颅内引流血管网络位于脑膜中，或大脑周围的膜，以及它与蛛网膜一起积极参与多年来，人们都知道将物质注射到大脑中。大脑进入头部和颈部的淋巴引流系统，但解剖学上在发现 Aβ 之前，研究人员还发现连接在很大程度上仍然是一个“黑匣子”。然而，颈部淋巴管的破坏导致了认知障碍。目前相关数据表明脑膜与痴呆有关。通过管理将内源性废物清除到全身循环来维持大脑健康。脑膜淋巴管与主要病理特征之间尚无明确的功能联系阿尔茨海默病，而且还不清楚淋巴功能如何受到损害我们的假设是，脑膜在疾病发生或进展过程中发挥着必要且特定的作用。我们提出从大脑中清除神经毒性焦谷氨酸-Aβ (pE3-Aβ) 和其他 Aβ 物种的作用。衰老过程中淋巴管和蛛网膜发生病理变化，从而促进阿尔茨海默氏病的发生或进展为了检验这一假设，我们采用了以下方法。 TgF344-AD 大鼠模型具有阿尔茨海默病的关键特征，该模型与大鼠杂交。表达荧光标记蛋白，使淋巴管的细节清晰可见。与此同时，我们正在系统地检查阿尔茨海默病中的人类脑膜，目标#1 将进行检查。淋巴清除的能量依赖机制，为药物提供新的潜在靶点目标#2将确认衰老过程中淋巴系统的解剖学相关性并调节其。目标 3 将确定脑膜系统的因果证明和可塑性的相关性。通过创建高分辨率图谱，研究 pE3-Aβ 和 Aβ 的脑膜清除对人类阿尔茨海默病的影响人类脑膜并使用蛋白质组学和生化分析来模拟清除途径。研究将为研究界提供宝贵的新工具，并促进治疗发现。