Deciphering Ang2/Tie2 signaling regulation of BBB disruption and neuroinflammation in Alzheimers disease

破译 Ang2/Tie2 信号对阿尔茨海默病 BBB 破坏和神经炎症的调节

基本信息

批准号：
10452152
负责人：
Minah Kim
金额：
$ 32.88万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452152
关键词：
AD transgenic mice ANGPT2 gene Aging Agonist Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer’s disease biomarker Amyloid beta-Protein Angiopoietin-2 Autopsy Binding Blood - brain barrier anatomy Blood Vessels Blood coagulation Blood specimen Brain Cell Aging Cell membrane Deposition Disease Disease Progression Endothelial Cells Endothelium Extravasation Fibrin Fibrinogen Foundations Functional disorder Gene set enrichment analysis Genes Genetic Goals Hemorrhage Human Impairment Inflammation Inflammatory Inflammatory Response Link Mediating Molecular Mus Neurodegenerative Disorders Pathogenesis Pathologic Pathway interactions Pericytes Plasma Process Production Proteins Regulation Resources Role Severities Signal Pathway Signal Transduction Signaling Molecule TIE-2 Receptor Testing Tg2576 Therapeutic Therapeutic Intervention Transgenic Mice Up-Regulation Work abeta accumulation age related aged amyloid pathology antagonist blood-brain barrier disruption brain endothelial cell brain tissue diagnostic biomarker experimental study genetic approach improved loss of function mouse model neuroinflammation neuron loss neurovascular new therapeutic target novel novel diagnostics novel therapeutic intervention potential biomarker preclinical study receptor targeted biomarker targeted treatment tool translational study

项目摘要

TITLE: Deciphering angiopoietin-2 regulation of BBB disruption and neuroinflammation in Alzheimer’s disease PROJECT SUMMARY Alzheimer’s disease (AD) is a fatal neurodegenerative disorder with limited therapeutic options thus necessitating the urgency to identify new drug targets for improved treatments. Increasing evidence has suggested that neuroinflammation contributes to and drives AD pathogenesis. In this context, the age-related disruption of blood–brain barrier (BBB), a protective and highly specialized endothelial cell membrane in the brain, can promote inflammatory processes. Therefore, identifying the molecular determinants of BBB disruption and neuroinflammation in aging, which can contribute to AD progression, is necessary to guide the identification of new therapeutic targets and potential biomarkers. Previous work has shown that the signaling molecule angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2 in endothelial cells, is a potent driver of vascular destabilization. Our previous work has demonstrated that under inflammatory conditions, Ang2 function switches from a Tie2 agonist to a Tie2 antagonist to promote vascular destabilization and leakage. However, the contribution of the Ang2/Tie2 signaling pathway to BBB disruption and neuroinflammatory processes in aging and AD progression is largely unknown. Our preliminary evidence shows that ANGPT2 (Ang2) levels are increased in the human late-stage AD brain as well as in brains of AD transgenic mice (5xFAD). Furthermore, we found that this Ang2 increase correlates with fibrinogen deposition and impaired pericyte coverage, both indicative of BBB disruption and associated with AD pathology. We will use mouse models of AD as well as human AD brain tissue and blood specimens from AD patients to determine the contribution of the Ang2/Tie2 pathway to BBB disruption in AD. In Aim 1, we will determine the involvement of Ang2/Tie2 signaling in the process of BBB disruption and neuroinflammation during aging. Studies will assess differences in Ang2/Tie2 signaling, BBB integrity, vascular leakage, and fibrinogen deposition in aging mice. Additionally, genetic gain- and loss-of-function strategies will be used to determine the significance of Ang2/Tie2 signaling in BBB integrity and neuroinflammation in these mice. In Aim 2, we will determine the significance of Ang2/Tie2 signaling in the regulation of BBB integrity and neuroinflammation during AD progression. Studies in AD mouse models combined with genetic approach will identify the significance of Ang2/Tie2 signaling in promoting BBB disruption, neuroinflammatory progression, and AD pathogenesis. Additionally, studies using human AD brain and blood specimens will determine if alterations in Ang2/Tie2 signaling are associated with BBB disruption, fibrinogen deposition, and AD pathology. Successful completion of this project will increase our basic understanding of novel regulators of neurovascular dysfunction and neuroinflammation in AD. This work will also provide a foundation for further preclinical studies and subsequent human translational studies to develop new therapeutic strategies and test novel diagnostic biomarkers for AD.

标题：破译血管生成素 2 对阿尔茨海默病 BBB 破坏和神经炎症的调节疾病项目概要阿尔茨海默病（AD）是一种致命的神经退行性疾病，治疗选择有限，因此越来越多的证据表明迫切需要确定新的药物靶点以改进治疗。表明神经炎症有助于并驱动 AD 发病机制，在这种情况下，与年龄相关。血脑屏障（BBB）的破坏，血脑屏障是大脑中的一种保护性且高度专业化的内皮细胞膜脑，可以促进炎症过程，因此，确定 BBB 的分子决定因素。衰老过程中的破坏和神经炎症可能导致 AD 进展，对于指导先前的工作表明，新的治疗靶点和潜在的生物标志物的鉴定。血管生成素-2 (Ang2) 分子与内皮细胞中的受体酪氨酸激酶 Tie2 结合，是一种我们之前的工作已经证明，在炎症条件下，血管不稳定的驱动力。在某些条件下，Ang2功能从Tie2激动剂转变为Tie2拮抗剂以促进血管不稳定然而，Ang2/Tie2 信号通路对 BBB 破坏和渗漏的贡献。衰老和 AD 进展中的神经炎症过程在很大程度上是未知的。显示 ANGPT2 (Ang2) 水平在人类晚期 AD 大脑以及 AD 大脑中增加此外，我们发现 Ang2 的增加与纤维蛋白原沉积相关。和周细胞覆盖受损，这两者都表明 BBB 破坏并与 AD 病理相关。使用 AD 小鼠模型以及人类 AD 脑组织和 AD 患者的血液样本确定 Ang2/Tie2 通路对 AD 中 BBB 破坏的贡献在目标 1 中，我们将确定 Ang2/Tie2 信号传导参与衰老过程中 BBB 破坏和神经炎症的过程。研究将评估 Ang2/Tie2 信号传导、血脑屏障完整性、血管渗漏和纤维蛋白原的差异此外，将使用遗传功能获得和丧失策略来确定。在目标 2 中，我们将了解 Ang2/Tie2 信号传导在这些小鼠 BBB 完整性和神经炎症中的重要性。确定 Ang2/Tie2 信号传导在调节 BBB 完整性和神经炎症中的重要性 AD 小鼠模型与遗传方法相结合的研究将确定 AD 进展过程中的相关因素。 Ang2/Tie2 信号传导在促进 BBB 破坏、神经炎症进展和 AD 中的重要性此外，使用人类 AD 大脑和血液样本的研究将确定是否发生改变。 Ang2/Tie2 信号传导与 BBB 破坏、纤维蛋白原沉积和 AD 病理学相关。该项目的完成将增加我们对神经血管新型调节剂的基本了解这项工作也将为进一步的临床前研究奠定基础。以及随后的人类转化研究，以开发新的治疗策略并测试新的诊断方法 AD 的生物标志物。