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

• 批准号: 10631074
• 负责人: Christopher G. Janson
• 金额: $ 37.68万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 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/10631074
• 关键词: Abeta clearance; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Anatomy; Arachnoid Membrane; Arachnoid mater; Attention; Automobile Driving; Biochemical; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Cells; Cephalic; Cervical; Cervical lymph node group; Circulation; Clinical; Cognitive; Communities; Confocal Microscopy; Crossbreeding; 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 clearance; Lymphatic function; Lymphocyte; Maintenance; Maps; Measurement; Membrane; Meningeal; Meningeal lymphatic system; Meninges; Methods; Mitochondria; Modeling; Molecular; Mus; Neurons; Normal Cell; Pathologic; Pathway interactions; Patients; Peptides; Play; Post-Translational Protein Processing; Proteins; Proteomics; Protocols documentation; Pyroglutamate; Rattus; Regional Anatomy; Research; Research Personnel; Resolution; Rodent Model; Role; Route; Structure; System; Testing; Therapeutic; Time; Tissues; Translating; Viral Vector; Visualization; abeta accumulation; age effect; age related; brain health; clinically relevant; diagnostic tool; health management; healthy aging; human subject; in vivo; lymphatic drainage; lymphatic vasculature; lymphatic vessel; molecular diagnostics; mosaic; neurotoxic; neurovascular unit; novel; pharmacologic; prevent; protein biomarkers; sex; solute; targeted treatment; three dimensional cell culture; tissue processing; tool; uptake; vascular risk factor; wasting; β-amyloid burden

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清除有毒多肽，如淀粉样β蛋白(Aβ)的情况 受伤了。确定大脑清除能力受损的机制将会打开 减轻或预防阿尔茨海默病的治疗机会。该领域已经集中了大部分 它关注血管风险因素，如Aβ在血脑屏障的运输。尽管意义重大 尽管取得了进展，但Aβ脑清除受损的首要问题尚未得到解决。因此，有一个 需要考虑替代路线或清关机制。新近发现的脑膜 淋巴系统是Aβ清除受损和阿尔茨海默氏症之间缺失环节的主要候选对象 疾病。这个以前不为人知的颅内引流血管网络位于脑膜， 或围绕大脑的膜，以及它积极参与的蛛网膜层 清除大脑中的液体和溶质。多年来，人们都知道注入到人体内的物质 大脑进入头部和颈部的淋巴引流系统，但在解剖学上 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，连接 颈部淋巴管疾病会导致认知障碍。然而，淋巴引流之间的直接联系 痴呆症也从未得到证实。相关数据现在表明，脑膜参与了 通过管理将内源性废物排入体循环来维持大脑健康。还没有 脑膜淋巴管和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是如何受损的 在疾病开始或发展的过程中。我们的假设是脑膜起着必要的和特定的作用 在从大脑中清除神经毒性焦谷氨酸-Aβ(PE3-Aβ)和其他Aβ物种方面的作用。我们建议 淋巴管和蛛网膜的病理变化发生在衰老过程中，因此 促进阿尔茨海默病的开始或进展。为了检验这一假设，我们调整了 TgF344-AD大鼠模型，携带阿尔茨海默病的关键特征。这是与一只老鼠杂交的 表达荧光标记蛋白，以便淋巴血管以精致的细节可视化。在……里面 与此同时，我们正在系统地检查阿尔茨海默病患者的脑膜。目标#1将检查 淋巴清除的能量依赖机制，为药物提供新的潜在靶点 心理治疗。目标2将确认淋巴系统在衰老过程中的解剖学相关性，并将调节其 证明脑膜系统的因果关系和可塑性的功能。目标3将确立 脑膜清除剂PE3-Aβ和Aβ对人类阿尔茨海默病的清除 并使用蛋白质组学和生物化学分析来模拟清除途径。这些 研究将为研究界提供宝贵的新工具，并将使治疗发现成为可能。