Project Summary/Abstract Alzheimer's Disease (AD) and AD related disorders (ADRD) affect millions of people in the United States and are major contributors to dementia worldwide. Since neuroinflammation plays an integral role in AD/ADRD, we propose to expand our long-term NIA-funded research (R01 AG018859-19) to gain new knowledge about how advanced age and the gut-brain axis trigger the decline in cognitive function using our well-established clinically relevant murine model of cutaneous burn injury. Clinical and experimental evidence reveal that healthy aged subjects are in an elevated basal inflammatory state, referred to as “inflamm-aging,” which can contribute to deficits in tissue injury and repair. We, and others, believe that inflammaging is caused, in part, by translocation of bacterial products from the intestinal lumen and that exposure to these products triggers the production of pro-inflammatory cytokines and chemokines, including tumor necrosis factor alpha (TNF), interleukin (IL)-1β, IL-6, and C-C Motif Chemokine Ligand 2 (CCL2). Recently published work from our lab revealed that aged mice who sustain a scald burn injury have a greater breach in intestinal epithelial barrier integrity than younger mice given the same injury. Additionally, we found that this heightened intestinal response, and an alteration in the intestinal microbiome, both parallel a profound rise in inflammatory markers in the brain. Both neuroinflammation and burn injury in the aged population have been correlated with breaches in the blood brain barrier (BBB), delirium, and other signs of cognitive decline. From these observations, we hypothesize that increased gut leakiness and altered intestinal microbiome in aged mice after burn injury leads to heightened systemic inflammation and breach of the BBB, neuronal damage, and cognitive decline. To test this, we propose to examine BBB dysfunction, neuroinflammation and cognitive function in young and aged mice after burn injury by comparing the integrity of the BBB, the presence of gut-derived bacteria/lipopolysaccharide (LPS) in the brain, as well as the systemic circulation, and characterizing the activation of microglia and neuronal damage/death following injury. Moreover, we will monitor cognitive function in young and aged mice both before and after burn injury to allow us to correlate these behavioral tests with the aforementioned biomarkers of leakiness, inflammation, and neuronal damage. These studies will expand our understanding of how advanced age alters the gut in the context of burn injury and the impact of intestinal permeability on neuroinflammation, a hallmark of AD/ADRD. It is our hope that this work will lead to the development of novel therapies to treat the excessive inflammatory response and cognitive dysfunction seen in older patients suffering from traumatic injuries and a variety of other disorders.