The effect of exercise-linked fibronectin type III domain-containing protein 5 (FNDC5)/irisin on synaptic plasticity and memory defects in Alzheimer’s animal models
Leo Sher, M.D.
A research report, “Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models” is published in the January 2019 issue of Nature Medicine (1). Irisin is a myokine released into the circulation during physical exercise and is capable of stimulating adipocyte browning and thermogenesis in mice and humans. Irisin is cleaved from fibronectin type III domain-containing protein 5 (FNDC5), a transmembrane precursor protein expressed in muscle. FNDC5/irisin increases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, a brain area centrally involved in learning and memory. This raises the possibility that FNDC5/irisin could play a neuroprotective role in diseases of the central nervous system, such as Alzheimer’s disease.
The authors report that they investigated FNDC5/ irisin levels in the brain and cerebrospinal fluid (CSF) of individuals with Alzheimer’s disease and in mouse models of Alzheimer’s disease. The authors also tested a hypothesis that FNDC5/irisin could be a mediator of the positive influences of exercise on synaptic plasticity and memory in Alzheimer’s disease models.
The authors have observed that FNDC5/irisin levels are reduced in hippocampi and CSF of patients Alzheimer’s disease, and in experimental Alzheimer’s disease models. Knockdown of brain FNDC5/irisin damages long-term potentiation and novel object recognition memory in mice. On the contrary, enhancing brain levels of FNDC5/irisin rescues synaptic plasticity and memory in Alzheimer’s disease mouse models. The authors found that FNDC5/irisin mediates the protective actions of physical exercise on synaptic plasticity and memory in Alzheimer’s disease models. Peripheral overexpression of FNDC5/irisin rescues memory damage, whereas blockade of peripheral or brain FNDC5/irisin reduces the neuroprotective effects of physical exercise on synaptic plasticity and memory in Alzheimer’s disease mice.
This study shows that irisin may improve brain health and reduce the impairment and memory loss that occur during dementia. The authors suggest that bolstering brain FNDC5/irisin levels, either pharmacologically or via exercise, constitutes an innovative treatment strategy to protect and/or repair synapse function and prevent cognitive decline in Alzheimer’s disease. A limitation of this study is that the researchers used mice, and it is not known if exercise and irisin work similarly in people.
1. Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MAM, Abisambra JF, Tovar-Moll F, Mattos P, Arancio O, Ferreira ST, De Felice FG. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med. 2019 Jan;25(1):165-175.