Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models

Defective brain hormonal signaling has been associated with Alzheimer’s disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released upon cleavage of membrane-bound precursor protein FNDC5, also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impaired long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescued synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescued memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuated the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD.