PROJECT SUMMARY/ABSTRACT Neurological impairment caused by neurodegenerative diseases, such as Alzheimer’s disease (AD), is a major, growing health burden. Exercise has been shown in human studies and animal models to be neuroprotective in AD, a disease associated with an increased Amyloid beta (Aβ)-burden, neuroinflammation, and cognitive decline. Exercise reduces the Aβ-burden and neuroinflammation, and improves cognitive function in AD mouse models. Understanding the underlying molecular mechanism of these neuroprotective effects of exercise can lead to the development of 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. 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 three-dimensional (3D) human neural cell culture model of AD and an in vivo transgenic mouse model of AD and by using mechanistic molecular techniques, morphological studies, and behavioral testing. We will achieve this objective by addressing (Aim 1) whether irisin is neuroprotective in vitro by 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, and (Aim 3) by which cellular mechanism that occurs. Successful completion of these experiments will provide a better understanding of the molecular mechanisms whereby exercise provides neuroprotection in neurodegenerative diseases. In addition, it establishes a framework for how irisin could be used as a therapeutic to treat AD.