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

• Published in: Nature medicine Vol. 25; no. 1; pp. 165 - 175
• Main Authors: Lourenco, Mychael V., Frozza, Rudimar L., de Freitas, Guilherme B., Zhang, Hong, Kincheski, Grasielle C., Ribeiro, Felipe C., Gonçalves, Rafaella A., Clarke, Julia R., Beckman, Danielle, Staniszewski, Agnieszka, Berman, Hanna, Guerra, Lorena A., Forny-Germano, Letícia, Meier, Shelby, Wilcock, Donna M., de Souza, Jorge M., Alves-Leon, Soniza, Prado, Vania F., Prado, Marco A. M., Abisambra, Jose F., Tovar-Moll, Fernanda, Mattos, Paulo, Arancio, Ottavio, Ferreira, Sergio T., De Felice, Fernanda G.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2019; Nature Publishing Group
• Subjects: 631/378/1595; 631/378/2591/2592; 631/378/87; 692/617/375/365/1283; Adolescent; Adult; Advertising executives; Aged; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Analysis; Animal models; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Brain - pathology; Brain research; Cancer Research; Cerebrospinal fluid; Dementia; Disease Models, Animal; Down-Regulation; Exercise; Female; Fibronectin; Fibronectins; Fibronectins - cerebrospinal fluid; Fibronectins - genetics; Fibronectins - metabolism; Glucagon; Hippocampus; Hostages; Humans; Immunology; Impairment; Infectious Diseases; Insulin; Long-Term Potentiation; Male; Mass spectrometry; Membrane proteins; Memory; Memory Disorders - complications; Memory Disorders - physiopathology; Metabolic Diseases; Mice, Inbred C57BL; Middle Aged; Molecular Medicine; Neuronal Plasticity; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Object recognition; Pattern recognition; Peptides; Phenotypes; Physical Conditioning, Animal; Physical exercise; Plasma; Plasticity; Protein binding; Proteins; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; RNA, Messenger - genetics; RNA, Messenger - metabolism; Scientific imaging; Signal Transduction; Synaptic plasticity
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-018-0275-4

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 on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (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 impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates 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. Expression of the exercise-induced myokine irisin (FNDC5) is lower in patients with AD. Whereas knockdown of FNDC5/irisin is sufficient to induce learning and memory deficits, restoration of its expression can ameliorate these phenotypes in rodent models.