Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models
Authors: Soniza Alves-Leon
Paulo Mattos
Shelby Meier
Rudimar L Frozza
Marco A M Prado
Fernanda G De Felice
Mychael V Lourenco
Ottavio Arancio
Vania F Prado
Jose F Abisambra
Agnieszka Staniszewski
Letícia Forny-Germano
Fernanda Tovar-Moll
Rafaella A Gonçalves
Grasielle C Kincheski
Danielle Beckman
Donna M Wilcock
Lorena A Guerra
Hong Zhang
Sergio T Ferreira
Hanna Berman
Jorge M de Souza
Felipe C Ribeiro
Julia R Clarke
Guilherme B de Freitas
Journal: Nature Medicine (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Alzheimer's disease; Irisin; FNDC5; Synaptic plasticity; Memory impairment
Affiliations: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA., Oswaldo Cruz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Rio de Janeiro, Brazil., Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada., School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA., Division of Neurosurgery, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Robarts Research Institute, University of Western Ontario, London, Ontario, Canada., Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada., Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada., D'Or Institute for Research and Education , Rio de Janeiro, Brazil., Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. ., Department of Pathology & Cell Biology, Columbia University, New York, NY, USA. ., Department of Medicine, Columbia University, New York, NY, USA. ., Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ., Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ., Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada. ., Department of Psychiatry, Queen's University, Kingston, Ontario, Canada. .

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. 

Retracted: No

PubPeer comments:
 Published today in Molecular Metabolism (Albrecht et al., 2020; https: www.sciencedirect.com science article pii S2212877820300247; DOI: 10.1016 j.molmet.2020.01.016) ** Lourenco et al. [11] identified four immune-reactive bands of Fndc5 in protein extracts from mouse hippocampus at molecular weights between 27 and 75 kDa with a commercial antibody, and confirmed the presence of Fndc5 protein in all bands by mass spectrometry. This was interpreted as occurrence of multimers and or post-translationally modified Fndc5 forms in hippocampus [11]. However, detection of protein multimers should be largely reduced under denaturing electrophoresis conditions. ** , 
 Closer examination of Figure 1b and Supplemental Figure 1b show very different band intensities for all 4 bands identified, even though they represent the same tissue from the same animals using the same antibody against FNDC5. Can the authors explain this? Closer examination of Figure 1b - at a higher magnification of examination - does it appear that 1 image of the left 2 lanes has been spliced next to the right 2 lanes - there appears to be a distinct line running down the left-hand side of FNDC5 mouse hippocampus lanes. Are these data from 2 gels or 1 gel? If there has been rearrangement, without indication in the legends or texts, this contravenes the rules by Nature - see electrophoretic gels and blots. ,