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. Abisambra; Fernanda Tovar-Moll; Paulo Mattos; Ottavio Arancio; Sergio T. Ferreira; Fernanda G. De Felice

doi:10.1038/s41591-018-0275-4

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. Abisambra

Fernanda Tovar-Moll, Paulo Mattos, Ottavio Arancio, Sergio T. Ferreira, Fernanda G. De Felice

Research output: Contribution to journal › Article › peer-review

821 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 language	English
Pages (from-to)	165-175
Number of pages	11
Journal	Nature Medicine
Volume	25
Issue number	1
DOIs	https://doi.org/10.1038/s41591-018-0275-4
State	Published - Jan 1 2019

Bibliographical note

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

Funding

This work was supported by grants from Alzheimer Society of Canada (to F.G.D.F.) and the Weston Brain Institute (to F.G.D.F.), National Institute for Translational Neuroscience (INNT/Brazil) (465346/2014-6 to S.T.F. and F.G.F.), Human Frontier Science Program (to F.G.D.F.), International Society for Neurochemistry (CAEN 1B to M.V.L.), National Institutes of Health (NIH-R01NS049442 to O.A.), Canadian Institutes of Health Research (CIHR MOP 136940 and MOP 89919 to V.F.P. and M.A.M.P.), and from the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (451195/2017-5 to M.V.L., 406436/2016-9 to S.T.F., and 473324/2013-0 to F.G.D.F.) and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (202.817/2016 to M.V.L., 201.432/2014 to S.T.F., and 202.944/2015 to F.G.D.F.). R.L.F, G.B.d.F., G.C.K., F.C.R., J.R.C., D.B., and L.F.-G. were supported by fellowships granted by FAPERJ, CNPq, or Comissão de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil; financial code 001). S.M. was supported by an NIH T32 grant (AG057461). We acknowledge the University of Kentucky Alzheimer’s Disease Center and its Neuropathology Core, which is supported by NIH/NIA P30 AG028383, for brain samples. We thank W.L. Klein (Northwestern University) for the kind gift of oligomer-specific NU4 antibodies, B.M. Spiegelman (Harvard University) for sharing AdGFP and AdFNDC5 adenoviral constructs, and J. Wang (Queen’s University, Canada) for help with mass spectrometry analyses. We also thank A. Lepelley, M. Oliveira, M. Melo, A.C. Rangel, and the CENABIO team for technical and/or administrative assistance.

Funders	Funder number
Institute for Translational Neuroscience
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
University of Kentucky Alzheimer’s Disease Research Center
Weston Brain Institute
Alzheimer Society
International Human Frontier Science Program Organization
International Society for Neurochemistry	CAEN 1B
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro	201.432/2014, 202.944/2015, 202.817/2016
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS049442, R01NS091329
Conselho Nacional de Desenvolvimento Científico e Tecnológico	406436/2016-9, 451195/2017-5, 473324/2013-0
National Institutes of Health (NIH)	L32MD009205
INNT/Brazil	465346/2014-6
Canadian Institutes of Health Research	MOP 89919, MOP 136940
U.S. Department of Health & Human Services \| NIH \| National Institute on Aging (U.S. National Institute on Aging)	P30AG028383, T32AG057461
CAPES Foundation, Ministry of Education of Brazil	AG057461

ASJC Scopus subject areas

General Medicine
General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/s41591-018-0275-4

Cite this

Lourenco, M. V., Frozza, R. L., de Freitas, G. B., Zhang, H., Kincheski, G. C., Ribeiro, F. C., Gonçalves, R. A., Clarke, J. R., Beckman, D., Staniszewski, A., Berman, H., Guerra, L. A., Forny-Germano, L., Meier, S., Wilcock, D. M., de Souza, J. M., Alves-Leon, S., Prado, V. F., Prado, M. A. M., ... De Felice, F. G. (2019). Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nature Medicine, 25(1), 165-175. https://doi.org/10.1038/s41591-018-0275-4

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title = "Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer{\textquoteright}s models",

abstract = "Defective brain hormonal signaling has been associated with Alzheimer{\textquoteright}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.",

author = "Lourenco, \{Mychael V.\} and Frozza, \{Rudimar L.\} and \{de Freitas\}, \{Guilherme B.\} and Hong Zhang and Kincheski, \{Grasielle C.\} and Ribeiro, \{Felipe C.\} and Gon{\c c}alves, \{Rafaella A.\} and Clarke, \{Julia R.\} and Danielle Beckman and Agnieszka Staniszewski and Hanna Berman and Guerra, \{Lorena A.\} and Let{\'i}cia Forny-Germano and Shelby Meier and Wilcock, \{Donna M.\} and \{de Souza\}, \{Jorge M.\} and Soniza Alves-Leon and Prado, \{Vania F.\} and Prado, \{Marco A.M.\} and Abisambra, \{Jose F.\} and Fernanda Tovar-Moll and Paulo Mattos and Ottavio Arancio and Ferreira, \{Sergio T.\} and \{De Felice\}, \{Fernanda G.\}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

month = jan,

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doi = "10.1038/s41591-018-0275-4",

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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 2019, 'Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models', Nature Medicine, vol. 25, no. 1, pp. 165-175. https://doi.org/10.1038/s41591-018-0275-4

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AU - Frozza, Rudimar L.

AU - de Freitas, Guilherme B.

AU - Zhang, Hong

AU - Kincheski, Grasielle C.

AU - Ribeiro, Felipe C.

AU - Gonçalves, Rafaella A.

AU - Clarke, Julia R.

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AU - Staniszewski, Agnieszka

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AU - Guerra, Lorena A.

AU - Forny-Germano, Letícia

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AU - de Souza, Jorge M.

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AU - Prado, Vania F.

AU - Prado, Marco A.M.

AU - Abisambra, Jose F.

AU - Tovar-Moll, Fernanda

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AU - Ferreira, Sergio T.

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PY - 2019/1/1

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

Abstract

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ASJC Scopus subject areas

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