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

Mychael V. Lourenco, Rudimar L. Frozza, Guilherme B. de Freitas, Hong Zhang, Grasielle C. Kincheski, Felipe C. Ribeiro, Rafaella A. Gonçalves, Julia R. Clarke, Danielle Beckman, Agnieszka Staniszewski, Hanna Berman, Lorena A. Guerra, Letícia Forny-Germano, Shelby Meier, Donna M. Wilcock, Jorge M. de Souza, Soniza Alves-Leon, Vania F. Prado, Marco A.M. Prado, Jose F. AbisambraFernanda Tovar-Moll, Paulo Mattos, Ottavio Arancio, Sergio T. Ferreira, Fernanda G. De Felice

Research output: Contribution to journalArticlepeer-review

627 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)165-175
Number of pages11
JournalNature Medicine
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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