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

标题：破译血管生成素-2对阿尔茨海默病患者血脑屏障破坏和神经炎症的调节 疾病 项目总结 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 迫切需要确定新的药物靶点，以改进治疗。越来越多的证据表明 提示神经炎症在AD发病机制中起重要作用。在这方面，与年龄有关的 血脑屏障(BBB)的破坏，血脑屏障是一种保护性和高度专门化的内皮细胞膜 大脑，可以促进炎症过程。因此，确定血脑屏障的分子决定因素 衰老中的干扰和神经炎症可能导致AD的进展，这对于引导 识别新的治疗靶点和潜在的生物标志物。先前的研究表明，信号传递 血管生成素-2(Ang2)是一种与血管内皮细胞中的受体酪氨酸激酶Tie2结合的分子。 血管不稳定的有力推动者。我们之前的研究表明，在炎症性环境下 条件下，Ang2功能从Tie2激动剂转换为Tie2拮抗剂以促进血管失稳 和渗漏。然而，Ang2/Tie2信号通路在血脑屏障破坏和 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 结果表明，血管紧张素转换酶2(Ang2)水平在人类晚期AD脑中升高，在AD脑中也是如此 转基因小鼠(5xFAD)。此外，我们发现这种Ang2的增加与纤维蛋白原沉积有关。 周细胞覆盖受损，这两个指标都表明血脑屏障中断，并与AD病理有关。我们会 利用阿尔茨海默病小鼠模型和人类阿尔茨海默病患者脑组织和血液样本 确定Ang2/Tie2通路在AD血脑屏障破坏中的作用。在目标1中，我们将确定 Ang2/Tie2信号通路参与衰老过程中的血脑屏障破坏和神经炎症。 研究将评估Ang2/Tie2信号、血脑屏障完整性、血管渗漏和纤维蛋白原的差异。 在衰老小鼠体内的沉积。此外，还将使用遗传获得和功能丧失策略来确定 Ang2/Tie2信号在小鼠血脑屏障完整性和神经炎症中的意义。在目标2中，我们将 确定Ang2/Tie2信号在调节血脑屏障完整性和神经炎症中的意义 在AD进展期间。结合遗传学方法在AD小鼠模型上的研究将确定 Ang2/Tie2信号在促进血脑屏障破坏、神经炎性进展和AD中的意义 发病机制。此外，使用人类阿尔茨海默病大脑和血液样本的研究将确定 ANG2/Tie2信号与血脑屏障破坏、纤维蛋白原沉积和AD病理有关。成功 该项目的完成将增加我们对神经血管新调节剂的基本了解 阿尔茨海默病的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。 以及随后的人类翻译研究，以开发新的治疗策略和测试新的诊断 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.