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Nat Med. 2019 Jan;25(1):165-175. doi: 10.1038/s41591-018-0275-4. Epub 2019 Jan 7.

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

Author information

1
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
2
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
3
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
4
Oswaldo Cruz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Rio de Janeiro, Brazil.
5
Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada.
6
School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
7
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
8
Division of Neurosurgery, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
9
Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
10
Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.
11
Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada.
12
Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada.
13
D'Or Institute for Research and Education , Rio de Janeiro, Brazil.
14
Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
15
Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
16
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. oa1@cumc.columbia.edu.
17
Department of Pathology & Cell Biology, Columbia University, New York, NY, USA. oa1@cumc.columbia.edu.
18
Department of Medicine, Columbia University, New York, NY, USA. oa1@cumc.columbia.edu.
19
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ferreira@biof.ufrj.br.
20
Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. ferreira@biof.ufrj.br.
21
Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. fernanda.defelice@queensu.ca.
22
Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada. fernanda.defelice@queensu.ca.
23
Department of Psychiatry, Queen's University, Kingston, Ontario, Canada. fernanda.defelice@queensu.ca.

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.

PMID:
30617325
PMCID:
PMC6327967
DOI:
10.1038/s41591-018-0275-4
[Indexed for MEDLINE]
Free PMC Article

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