Cited by 935Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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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.·2019·Nature Medicine

DOI 10.1038/s41591-018-0275-4PMC PMC6327967

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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.

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Authors: 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., Abisambra, J. F., Tovar-Moll, F., Mattos, P., Arancio, O., Ferreira, S. T., & De Felice, F. G.
Affiliations: Universidade Federal do Rio de Janeiro (BR)
Columbia University (US)
Queen's University (CA)
University of Kentucky (US)
Western University (CA)
Columbia University Irving Medical Center (US)
Corresponding author: Arancio, Ottavio
Ferreira, Sergio T.
ORCID: Lourenco, Mychael V.
Frozza, Rudimar L.
Zhang, Hong
Kincheski, Grasielle C.
Ribeiro, Felipe C.
Gonçalves, Rafaella A.
Clarke, Julia R.
Beckman, Danielle
Staniszewski, Agnieszka
Berman, Hanna
Meier, Shelby
Wilcock, Donna M.
Prado, Marco A. M.
Abisambra, Jose F.
Tovar-Moll, Fernanda
Mattos, Paulo
Arancio, Ottavio
Ferreira, Sergio T.
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2019-01
Volume: 25
Issue: 1
Pages: 165-175
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-018-0275-4
PMC: PMC6327967
OpenAlex: W2905067650
Cited by: 935
References: 71
Citations by year: 2026: 109 · 2025: 137 · 2024: 132 · 2023: 153 · 2022: 138 · 2021: 109 · 2020: 96 · 2019: 59
FWCI: 45.55
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
Scholarship@Western (Western University) (submittedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
Funders: Northwestern University
Harvard University
Weston Brain Institute
Alzheimer Society
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Queen's University
Conselho Nacional de Desenvolvimento Científico e Tecnológico (Code 001, 406436/2016-9, 465346/2014, 465346/2014–6, 2013‐0, 473324/2013-0)
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (201.432/2014, 202.817/2016, 202.944/2015)
International Society for Neurochemistry (CAEN 1B)
National Institutes of Health (AG028 383, T32 grant)
Institute for Translational Neuroscience (465346)
Canadian Institutes of Health Research (89919, MOP89919)
National Institute on Aging (AG-028383, P30AG028383, AG057461, T32AG057461)
National Institute of Neurological Disorders and Stroke (R01NS049442, R01NS091329)
National Institute on Minority Health and Health Disparities (L32 MD009205)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: FNDC5, irisin, Alzheimer's disease, physical activity, myokines, synaptic plasticity, long-term potentiation, memory impairment, hippocampus, cerebrospinal fluid, neuroprotection, learning and memory impairment
MeSH terms: Adolescent, Adult, Aged, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Fibronectins, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Middle Aged, Neuronal Plasticity, Physical Conditioning, Animal, Recombinant Proteins, RNA, Messenger, Signal Transduction, Down-Regulation, Long-Term Potentiation, Neuroprotective Agents

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

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