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.

阿尔茨海默氏病是一种疾病，在这种情况下，淀粉样蛋白β（Aβ）等有毒肽的大脑清除率是受损。确定大脑清除遭到损害的机制将打开衰减或预防阿尔茨海默氏病的治疗机会。该领域已经集中了很多它注意在血脑屏障上的血管危险因素（例如Aβ转运）上的关注。尽管很重要进展，尚未解决Aβ脑清除受损的总体问题。那有一个需要考虑清除的替代途径或机制。最近发现的脑膜淋巴系统是Aβ清除和阿尔茨海默氏症受损之间缺失联系的主要候选者疾病。以前无法识别的颅内引流容器网络位于脑膜中，或大脑周围的膜，以及蛛网膜膜，它积极参与从大脑中清除流体和太阳。多年以来，人们已经注入了物质大脑进入头部和颈部的淋巴引流系统，但解剖学连接在很大程度上仍然是一个“黑匣子”。在发现Aβ之前，研究人员还发现宫颈淋巴细胞药导致认知障碍。但是，淋巴引流之间的直接联系从未确立痴呆症。现在的相关数据表明脑膜参与通过管理将内源性废物清除到全身循环中来维持大脑健康。然而脑膜淋巴细胞和主要病理特征之间没有明确的功能联系阿尔茨海默氏病，此外，尚不清楚淋巴功能将如何受到损害在疾病开始或进展过程中。我们的假设是，脑膜发挥了必要而特定的作用从大脑中清除神经毒性的焦谷氨酸Aβ（PE3-Aβ）和其他Aβ物种方面的作用。我们建议淋巴管和蛛网膜膜的病理变化发生在衰老过程中，从而促进阿尔茨海默氏病的倡议或进展。为了检验这一假设，我们改编了具有阿尔茨海默氏病关键标志的TGF344-AD大鼠模型。这是用大鼠交叉的表达荧光标记蛋白，以便将淋巴管可视化。在平行于我们正在系统地检查阿尔茨海默氏病中的人类脑膜。 AIM＃1将检查能源依赖性机制是淋巴清除的基础机制，以提供药物的新潜在靶标治疗。 AIM＃2将确认衰老中淋巴系统的解剖相关性，并将调节其功能以证明脑膜系统的因果关系和可塑性。 AIM＃3将建立相关性通过创建高分辨率图，PE3-Aβ和Aβ的脑膜清除对人类阿尔茨海默氏病人类脑膜并使用蛋白质组学和生化分析来建模清除途径。这些研究将为研究社区提供宝贵的新工具，并将实现治疗发现。