PROJECT SUMMARY/ABSTRACT Cognitive impairment caused by aging or neurodegenerative disease is a major and growing health burden. Alzheimer's disease alone affects an estimated 5.5 million Americans today. Effective treatment options for Alzheimer?s disease are very limited. Interestingly, studies in both, human subjects and animal models have demonstrated that physical activity and exercise can improve cognitive function in these conditions, in part by increasing de novo neurogenesis in the hippocampus. Yet, developing new drugs based on stimulating neurogenesis will require a much deeper understanding of these exercise interventions on a molecular level. Recent research has highlighted the importance of the neurogenic stem cell niche in the regulation of adult hippocampal neurogenesis. The stem cell niche, i.e. the local microenvironment around the stem cells, supports the stemness of the stem cells, stimulates their proliferation, and regulates survival of immature neurons until their successful integration into the circuit. Secreted factors play a key role in this cellular-cross talk and they represent attractive druggable targets. If we can identify these mediators, they could be used to develop therapeutics to stimulate adult hippocampal neurogenesis and thereby cognitive function. Our initial work that identified FNDC5 and its secreted form ?irisin? as such important mediators of the benefits of exercise. Taken together, we hypothesize that exercise increases the neurogenic potential of the stem cell niche in the hippocampus and that the identification of those neurogenic mediators is a promising strategy to combat cognitive decline in aging or neurodegenerative disease. We therefore aim to dissect the adaptive response of the neurogenic stem cell niche in exercise in the dentate gyrus, the hippocampal region where new neurons are generated, using a novel transcriptional approach. As exercise intervention, we will use volunteer free-wheel running in mice, which has been shown to be highly effective for increasing neurogenesis in the hippocampus and improving spatial learning and memory. Secreted factors from the stem cell niche will be identified by supervised computational analysis. Next, we will test whether these pathways are required for the exercise-induced neurogenesis or improvements in spatial learning and memory. Lastly, we will evaluate their neurogenic and neuroprotective potential in a transgenic mouse model of Alzheimer?s disease. Successful completion of the proposed experiments will provide a better understanding of the molecular mechanisms whereby exercise affects neurogenesis and improves cognitive function. In addition, it will establish a framework of the therapeutic potential of secreted factors from the stem cell niche to treat cognitive decline in Alzheimer?s? disease and aging.