Xenon gas treatment to modulate microglia in neurodegenerative diseases

第一阶段申请 (STTR计划PAS-19-317) “用氙气治疗神经退行性疾病中的小胶质细胞” 摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病。新出现的证据表明 大脑免疫系统的动态平衡失调，特别是由小胶质细胞协调的免疫系统，在 在疾病的发生和发展中起着重要作用。小胶质细胞的功能在健康的大脑中得以维持 在阿尔茨海默病的大脑中处于病理性的失调状态。突出的遗传风险因素，载脂蛋白E，涉及 小胶质细胞功能。我们最近发现了一个独特的动态平衡小胶质细胞的分子特征，并已经 开发了强大的工具来研究健康和疾病中的小胶质生物学。我们还确定了 APOE信号在调节与神经退行性变相关的新的小胶质细胞亚群和小胶质细胞中的作用 人AD脑内神经炎性抗体斑块周围，我们称之为MGnD。主要问题涉及 以小胶质细胞为基础的治疗AD的方法是如何调节小胶质细胞的表型和功能。保存 Aβ诱导神经细胞凋亡以及恢复驻留小胶质细胞的稳态功能 对恢复大脑功能至关重要。 该方案的目的是验证氙气(Xe)对AD小鼠小胶质细胞的调节能力 模型和人类，这将导致新的AD治疗方法的发展。Xe目前用于人类患者 作为麻醉剂和神经保护剂用于脑损伤的治疗。Xe穿透血脑屏障，这 可以让它成为有效的治疗手段。我们的初步数据表明，在急性和AD小鼠模型中，Xe 通过吸入传递调节大脑小胶质细胞，并以止血的形式保存它。在本建议书中 我们希望进一步验证Xe对AD模型小鼠体内小胶质细胞的作用以及在神经生殖人类中的作用 小胶质细胞。我们将从以下几个方面阐述我们的假设： 目的1：探讨氙气治疗是否影响神经退行性变的表型和功能 APP-PS1小鼠的小胶质细胞。 目的2：验证氙气治疗是否影响神经退行性变患者的表型和功能 小胶质细胞。 根据这些工作的结果，我们将能够开发吸入系统和方案 落实阿尔茨海默病治疗方法。

PHASE I APPLICATION (STTR Program PAS-19-317) “Xenon gas treatment to modulate microglia in neurodegenerative diseases” ABSTRACT Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays a significant role in the onset and progression of the disease. The microglial function is maintained in healthy brain and is pathogenically dysregulated in AD brain. The prominent genetic risk factors, APOE, is involved in microglial function. We have recently identified a unique molecular signature for homeostatic microglia and have developed robust tools to investigate microglial biology in health and disease. We also identified a role for the APOE-signaling in the regulation of a new microglial subset associated with neurodegeneration and in microglia surrounding neuritic Ab-plaques in human AD brain, which we have termed MGnD. The major question relates to microglia-based approach to treat AD is how to modulate microglia phenotype and function. Preservation of neuronal cells from Aβ induced apoptosis as well as restoration of resident microglial homeostatic function is critical for the restoration of brain function. The goal of this proposal is to validate the Xenon (Xe) gas ability to modulate microglia in AD mouse model and human, that will lead to development of novel AD treatment. Xe is currently used in human patients as an anesthetic and as a neuroprotectant in treatment of brain injuries. Xe penetrates blood brain barrier, which can make it effective therapeutic. Our preliminary data demonstrated in acute and AD mouse models that Xe delivered through inhalation modulates brain microglia and preserve it in the hemostatic form. In this proposal we would like to further validate Xe action on microglia in-vivo in AD mice model and in neurogenerative human microglia. We will address our hypothesis in the following aims: Aim 1: Investigate whether Xe-gas treatment affects phenotype and function of neurodegenerative microglia in APP-PS1 mice. Aim 2: Validate whether Xe-gas treatment affects phenotype and function of neurodegenerative human microglia. Based on results of these work we will be able to develop the inhalation system and protocol for implementation of the therapeutic method for AD treatment.