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.

Narrative Microglia, the primary immune cells and the sensor of the brain's health, play a pivotal role in the maintenance of brain homeostasis, but lose their functions during the course of aging and neurodegenerative diseases. The goal of this proposal is to develop treatment for protection neurons from apoptosis and microglia from acquiring neurodegenerative phenotype using noble gas xenon (Xe), which can ultimately become a novel AD therapy. We plan to investigate the protective effect of Xe on the AD brain homeostasis and design a method for Xe delivery in the optimal concentration.