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

标题：解读血管生成素-2对阿尔茨海默氏症BBB破坏和神经炎症的调节 疾病 项目摘要 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 迫切需要鉴定用于改进治疗的新药物靶点。越来越多的证据 表明神经炎症有助于并驱动AD发病机制。在这方面，与年龄有关的 破坏血脑屏障（BBB），血脑屏障是一种保护性和高度特化的内皮细胞膜， 大脑，可以促进炎症过程。因此，确定BBB的分子决定因素 破坏和神经炎症，这可能有助于AD的进展，是必要的，以指导 鉴定新的治疗靶点和潜在的生物标志物。以前的研究表明， 分子血管生成素-2（Ang 2）结合内皮细胞中的受体酪氨酸激酶Tie 2，是一种血管生成素。 血管不稳定的潜在驱动因素。我们以前的工作已经证明，在炎症的情况下， 在某些条件下，Ang 2功能从Tie 2激动剂转换为Tie 2拮抗剂以促进血管不稳定 和泄漏。然而，Ang 2/Tie 2信号通路对血脑屏障破坏的作用和 在衰老和AD进展中的神经炎症过程在很大程度上是未知的。我们的初步证据 显示ANGPT 2（Ang 2）水平在人类晚期AD脑中以及在AD脑中增加 转基因小鼠（5xFAD）。此外，我们发现Ang 2的增加与纤维蛋白原的沉积相关， 和受损的周细胞覆盖，这两者都指示BBB破坏并与AD病理学相关。我们将 使用AD的小鼠模型以及来自AD患者的人类AD脑组织和血液样本， 确定AD中Ang 2/Tie 2途径对BBB破坏的贡献。在目标1中，我们将确定 Ang 2/Tie 2信号传导参与衰老期间BBB破坏和神经炎症过程。 研究将评估Ang 2/Tie 2信号传导、BBB完整性、血管渗漏和纤维蛋白原的差异 在衰老小鼠体内沉积。此外，遗传获得和功能丧失策略将用于确定 Ang 2/Tie 2信号传导在这些小鼠中的BBB完整性和神经炎症中的意义。在目标2中，我们将 确定Ang 2/Tie 2信号传导在BBB完整性和神经炎症调节中的意义 在AD进展期间。结合遗传学方法的AD小鼠模型研究将确定 Ang 2/Tie 2信号在促进BBB破坏、神经炎症进展和AD中的意义 发病机制此外，使用人类AD脑和血液标本的研究将确定 Ang 2/Tie 2信号传导与BBB破坏、纤维蛋白原沉积和AD病理学相关。成功 本项目的完成将增加我们对神经血管的新型调节剂的基本理解 功能障碍和神经炎症。这项工作也将为进一步的临床前研究提供基础 以及随后的人类转化研究，以开发新的治疗策略和测试新的诊断方法。 AD的生物标志物。

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.