The Impact of the Exercise Hormone Irisin on Astrocytes in Alzheimer's Disease
In this proposal, we seek to investigate the neuroprotective effects of the novel exercise-hormone FNDC5/irisin in Alzheimer’s disease (AD). Exercise has been shown in animal models and clinical studies in humans to be neuroprotective in AD. A hormone called irisin cleaved from fibronectin type III domain-containing protein 5 (FNDC5) is a novel exercise-induced myokine which regulates energy metabolism and improves mitochondrial function in adipose tissue. However, it has remained unclear whether and how irisin affects AD pathogenesis at the cellular and molecular levels. There is growing evidence that exercise-induced enhancement or protection of cognitive function may be associated with the inhibitory effect of exercise on neuroinflammation and amyloid pathology. Importantly, astrocytes, one of the most dominant cell types in the brain and key regulators of neuroinflammation, play an important role in mediating Aβ clearance from the AD brain. The goal of this project is to identify the mechanism(s) by which astrocytes mediate the effects of irisin on AD by utilizing a novel tool with 3D human neural cell culture models of AD and AD mouse models. Understanding the possible mechanisms through which physical activity may protect against AD is necessary for the development of alternative approaches that build on the beneficial effects of exercise in the brain. If irisin can offer exercise-mimicking benefits in AD, it will have high potential as a novel druggable target that holds promise for patients, to battle an increasingly sedentary lifestyle, especially for elderly patients with difficulties of doing exercise.