PROJECT SUMMARY/ABSTRACT This application titled “Exploring irisin as a novel target for Alzheimer’s Disease” is submitted in response to NIH PAR-16-042: Drug Discovery for Nervous System Disorders (R21). Neurological impairment caused by neurodegenerative diseases, such as Alzheimer’s disease (AD), is a major and growing health burden. Exercise has been shown in human studies and animal models to be neuroprotective in AD. AD is associated with an increased Amyloid beta (Aβ)-burden, impaired hippocampal neurogenesis, and cognitive decline. Exercise reduces the Aβ-burden, restores neurogenesis, and improves cognitive function in AD mouse models. Understanding the underlying molecular mechanism of these neuroprotective effects of exercise has the potential for developing innovative therapeutic approaches for this disorder. Our previously published data identified the novel exercise hormone FNDC5 (fibronectin-domain III containing 5) and its secreted form irisin as a prime candidate to mediate part of the neuroprotective effects of exercise. We have shown that irisin is an exercise-induced hormone in mice and humans that mediates (part of) the beneficial effects of exercise on the brain. Notably, the elevation of circulating irisin levels was sufficient to induce the expression of the important neurotrophin Bdnf and other neuroprotective genes in the hippocampus. Furthermore, the addition of recombinant irisin to a three-dimensional (3D) human neural cell culture model of AD reduced neuronal cell death. However, further mechanistic studies on how irisin is neuroprotective are required before irisin could be used therapeutically to treat cognitive decline in AD. Based on these data, we hypothesize that irisin has neuroprotective effects in AD models in vivo and in vitro. The objective for this proposal is to rigorously test this hypothesis by integrating an in vitro 3D human neural cell culture model of AD and an in vivo transgenic mouse model of AD and using mechanistic molecular techniques, morphological studies, and behavioral testing. We will achieve this objective by addressing (Aim 1) whether irisin is neuroprotective in vitro using a 3D human neural cell culture model of AD and (Aim 2) whether irisin is neuroprotective in vivo using a transgenic mouse model of AD. Successful completion of these experiments will provide a better understanding of the molecular mechanisms whereby exercise provide neuroprotection in neurodegenerative diseases. In addition, it establishes a framework for how irisin could be used as a therapeutic to treat AD.