Muscle-Brain Crosstalk in Alzheimer's Disease: Exercise-Associated FNDC5/Irisin Pathways in Preclinical Models - A...

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, neuroinflammation, and altered amyloid-β processing. Growing evidence suggests that physical exercise exerts neuroprotective effects partly mediated by myokines released from skeletal muscle. Among these, irisin, a cleavage product of fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a potential component of muscle-brain communication involved in neuroplasticity and memory-related pathways. This systematic review summarizes evidence from preclinical in vivo studies investigating exercise-induced FNDC5 expression and irisin-related signaling pathways in experimental models of AD. A literature search was conducted in PubMed and EMBASE following PRISMA guidelines to identify studies evaluating the effects of physical exercise on FNDC5 expression, irisin-related pathways, and cognitive outcomes in animal models of AD. Ten preclinical studies met the inclusion criteria and were included in the qualitative synthesis, encompassing both behavioral and mechanistic evidence. Overall, the evidence indicates that physical exercise was associated with increased FNDC5 expression, activation of irisin-related pathways, and downstream neuroprotective mechanisms including PPARGC1A, AMPK, SIRT1, and BDNF signaling. These molecular adaptations were associated with improvements in synaptic plasticity, reductions in neuroinflammation and oxidative stress, and attenuation of amyloid-related pathology. Behavioral assessments across multiple paradigms also demonstrated improvements in learning and memory following exercise interventions. Collectively, the available preclinical evidence suggests that FNDC5/irisin-related signaling is associated with neuroprotective effects of physical exercise in experimental models of AD as part of a broader exercise-induced response. Further studies are needed to clarify the underlying mechanisms and translational relevance of this pathway in AD.