Xenon gas treatment to modulate microglia in neurodegenerative diseases

第一阶段申请 (STTR程序PAS-19-317） “氙气治疗调节神经退行性疾病中的小胶质细胞” 摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的神经退行性疾病。新出现的证据显示 大脑免疫系统的稳态失调，特别是由小胶质细胞精心策划的， 在疾病的发生和发展中起重要作用。小胶质细胞的功能在健康的大脑中得以维持 并且在AD脑中病理性失调。突出的遗传风险因素，APOE，涉及 小胶质细胞功能我们最近已经确定了一个独特的分子标记的稳态小胶质细胞， 开发了强大的工具来研究健康和疾病中的小胶质细胞生物学。我们还确定了 APOE信号在与神经变性相关的新的小胶质细胞亚群和小胶质细胞中的调节 在人类AD脑中的周围神经炎性Ab斑块，我们将其称为MGnD。主要的问题是 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诱导的神经元细胞凋亡以及小胶质细胞稳态功能的恢复， 对恢复大脑功能至关重要 本研究的目的是验证氙气对AD小鼠小胶质细胞的调节作用 模型和人类，这将导致新的AD治疗的发展。目前用于人类患者 作为麻醉剂和神经保护剂用于治疗脑损伤。它能穿透血脑屏障， 可以使其有效治疗。我们的初步数据表明，在急性和AD小鼠模型中， 通过吸入递送的药物调节脑小胶质细胞并将其以止血形式保存。本提案中 我们希望进一步验证在AD小鼠模型和神经变性人类中对小胶质细胞的体内作用 小胶质细胞我们将在以下目标中阐述我们的假设： 目的1：研究Xe-gas治疗是否影响神经退行性变的表型和功能。 APP-PS1小鼠中的小胶质细胞。 目的2：探讨Xe-gas治疗是否影响神经退行性变人类的表型和功能 小胶质细胞 基于这些工作的结果，我们将能够开发吸入系统和方案， 用于AD治疗的治疗方法的实施。

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.