Administrative Supplement Application PA-20-272 Xenon gas treatment to modulate microglia in neurodegenerative diseases (R41AG073059) ABSTRACT ABSTRACT FROM ORIGINAL APPLICATION 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 Aβ-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. The goal of the original proposal was to investigate the Xenon (Xe) gas treatment to modulate microglia in AD mouse models and human iPSCs-derived microglia transplanted in humanized AD mice. 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 original specific aims were as follow: 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. SUPPLEMENTAL APPLICATION INFORMATION: To make competitive Phase II application and transition to clinical trial, we are planning to hold a pre-IND meeting with FDA. Developing such pre-IND meeting application was not a part of the original Phase I specific aims, but is closely connected. This new administrative supplement request will increase the likelihood to achieve additional critical R&D milestones in the technology development pathway to make us more competitive for Phase II application and ultimately for raising private-sector capital. The proposed scope of this additional supplement is within the overall scientific scope of the parent grant, which we will be able to complete by end of August 2022. The pre-IND submission package should include results of the originally proposed work and should address the following new specific aims: Aim 1: Determine PK/PD of Xenon inhalation treatment in an acute model of neurodegeneration and in APP/PS1 mice. The primary goal of our current efforts is to translate Xenon technology for testing in human AD patients. To prepare a competitive Phase II application for translation to humans, it is crucial to establish parameters of dosing base...