PROJECT SUMMARY/ABSTRACT Neurological impairment caused by aging or neurodegenerative diseases, such as Alzheimer’s disease (AD) is a major and growing health burden. Despite best efforts, traditional approaches to develop effective therapies have been largely unsuccessful. Interestingly, studies in both human subjects and animal models have shown that physical activity, especially endurance exercise, can improve cognitive function, mainly learning and memory, in part by enhancing adult neurogenesis in the hippocampus. Recent studies have highlighted the importance of secreted factors in cell-to-cell and cross-organ talks in exercise. The secreted factors that mediate the cognitive benefits of exercise represent very attractive drug targets. Our previously published data identified the novel exercise hormone irisin, the cleaved and secreted from of FNDC5 (fibronectin-domain III containing 5), as a prime candidate contributing to the cognitive benefits of exercise. Based on this preliminary data, we hypothesize is that FNDC5, through its secreted form irisin, acts as a critical regulator linking exercise to adult hippocampal neurogenesis resulting in improvements in cognitive function. Our goal is to rigorously test this hypothesis by integrating mechanistic molecular techniques, functional and morphological studies, and behavioral testing in genetic mouse models. We will achieve this goal by addressing the following three Specific Aims: In Aim 1, we will determine whether muscle-derived irisin is required for exercise-induced improvement in cognitive function. In Aim 2, we will test if irisin is the active form to mediate the beneficial effects of exercise. In Aim 3, we will elucidate whether peripheral elevation of irisin is sufficient to improve cognitive function in aging mouse models. Successfully completing these experiments will provide a better understanding of the molecular mechanism whereby exercise affects adult hippocampal neurogenesis and improves cognitive function. In addition, this project will establish a framework for potentially using irisin to treat cognitive decline in aging or AD.