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Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models
Open accessAbstract
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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“For example, cathepsin B and fibronectin type III domain containing protein 5 (FNDC5)/irisin have been shown to enter the brain and enhance neurogenesis and cognition.287”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [287]
In the citing paper
“Irisin administration in a mouse model of Alzheimer disease improves synaptic plasticity and memory function155,156.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [155]
In the citing paper
“We used several commercial ELISA/EIAs employed in the field to quantify plasma irisin field 12, but they measured the same “irisin” concentration in the plasma of F5KO and WT mice, indicating sensitivity or specificity issues (Extended Data Fig. 1d, e).”
From Exercise hormone irisin is a critical regulator of cognitive function (2021) · cites this paper as [12]
In the citing paper
“Moreover, irisin of central (hippocampal) and peripheral origin has been recently shown to promote an increase in cognitive function 119, further highlighting the potential benefits of exercise on healthspan.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [119]
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Metadata
- 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
- Published
- 2019-01
- Volume
- 25
- Issue
- 1
- Pages
- 165-175
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- 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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