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

Nature Medicine volume 25, pages 165–175 (2019)Cite this article

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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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Fig. 1: CNS FNDC5/irisin is reduced in AD.
Fig. 2: Brain FNDC5/irisin is reduced in AD models.
Fig. 3: Downregulation of brain FNDC5/irisin impairs synaptic plasticity and object recognition memory in mice.
Fig. 4: Brain FNDC5/irisin rescues defective synaptic plasticity and memory in AD mice.
Fig. 5: Irisin triggers the brain cAMP–PKA–CREB signaling pathway.
Fig. 6: FNDC5/irisin mediates the beneficial effects of exercise on synaptic plasticity and memory.

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Data availability

Mass spectrometry raw data (Fig. 1 and Extended Data Fig. 1) and full blots (Fig. 2 and Extended Data Figs. 3,4, and 10) are available as source data files accompanying this article. Additional data that support the findings of this study are available from the corresponding author upon reasonable request. Requests of datasets obtained from human research will be subject to additional review steps by the IRB that has granted permit for a particular research. Please contact the corresponding authors for additional information.

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Acknowledgements

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.

Author information

Author notes

  1. These authors contributed equally: Rudimar L. Frozza, Guilherme B. de Freitas.

Authors and Affiliations

  1. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Mychael V. Lourenco, Rudimar L. Frozza, Guilherme B. de Freitas, Grasielle C. Kincheski, Felipe C. Ribeiro, Julia R. Clarke, Danielle Beckman, Lorena A. Guerra, Letícia Forny-Germano, Sergio T. Ferreira & Fernanda G. De Felice

  2. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Mychael V. Lourenco, Grasielle C. Kincheski, Felipe C. Ribeiro, Lorena A. Guerra & Sergio T. Ferreira

  3. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Mychael V. Lourenco, Hong Zhang, Agnieszka Staniszewski, Hanna Berman & Ottavio Arancio

  4. Oswaldo Cruz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Rio de Janeiro, Brazil

    Rudimar L. Frozza

  5. Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada

    Guilherme B. de Freitas, Rafaella A. Gonçalves & Fernanda G. De Felice

  6. School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Julia R. Clarke

  7. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA

    Shelby Meier, Donna M. Wilcock & Jose F. Abisambra

  8. Division of Neurosurgery, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Jorge M. de Souza & Soniza Alves-Leon

  9. Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Jorge M. de Souza & Soniza Alves-Leon

  10. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

    Vania F. Prado & Marco A. M. Prado

  11. Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada

    Vania F. Prado & Marco A. M. Prado

  12. Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada

    Vania F. Prado & Marco A. M. Prado

  13. D’Or Institute for Research and Education , Rio de Janeiro, Brazil

    Fernanda Tovar-Moll & Paulo Mattos

  14. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Fernanda Tovar-Moll

  15. Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Paulo Mattos

  16. Department of Pathology & Cell Biology, Columbia University, New York, NY, USA

    Ottavio Arancio

  17. Department of Medicine, Columbia University, New York, NY, USA

    Ottavio Arancio

  18. Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada

    Fernanda G. De Felice

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  1. Mychael V. Lourenco
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  2. Rudimar L. Frozza
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Contributions

M.V.L., R.L.F., O.A., S.T.F., and F.G.D.F. designed the study. M.V.L., R.L.F., G.B.d.F., H.Z., G.C.K, F.C.R., R.A.G., J.R.C., D.B., A.S., H.B., L.A.G., L.F.-G., S.M., and J.F.A. performed the research. M.V.L., R.L.F., G.B.d.F., H.Z., D.B., A.S., S.M., J.F.A., O.A., S.T.F., and F.G.D.F. analyzed the data. J.F.A., D.M.W., J.M.d.S., S.A.-L., V.F.P., M.A.M.P., F.T.-M., P.M., and O.A. contributed the reagents, materials, and analysis tools. M.V.L., R.L.F., G.B.d.F., A.S, J.F.A., F.T-M., P.M., O.A., S.T.F., and F.G.D.F. analyzed and discussed the results. M.V.L., R.L.F., S.T.F., and F.G.D.F. wrote the manuscript.

Corresponding authors

Correspondence to Ottavio Arancio, Sergio T. Ferreira or Fernanda G. De Felice.

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The authors declare no competing interests.

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Extended data

Extended Data Fig. 1 Validation of anti-FNDC5 for detection of brain FNDC5/irisin.

a, Antibody blocking assay. Previous incubation of anti-FNDC5 (Abcam; ab131390) with increasing molar ratios of recombinant irisin (Adipogen; AG-40B-0136) reduces the signal of recombinant irisin detected by immunoblotting. The experiment was repeated 4 times with similar results. b, Left, Immunoblot of mouse hippocampus homogenate probed with anti-FNDC5. Immunolabeled bands 1–4 (see Results) were used to guide excision of the corresponding bands from the other half of the SDS–PAGE gel that had not been electroblotted (right). Band excision was guided by overlaying the unstained gel onto an image of the developed immunoblot (right panel). Excised bands were subjected to in-gel tryptic digestion followed by mass spectrometry analysis, as described in the Methods. Peptides identified by mass spectrometry in each band are indicated. c, Full-length FNDC5 amino acid sequence. The sequence corresponding to irisin is underlined. Peptides identified by mass spectrometry in excised bands are highlighted in green (bands 1, 2 and 3) or blue (band 4). d, Antibody used in the Phoenix ELISA kit (EK-067-29) recognizes recombinant irisin expressed in CHO cells (Adipogen; AG-40B-0136). The experiment was repeated 3 times with similar results. See Source Data 1 for original data.

Extended Data Fig. 2 CSF and plasma irisin correlations.

a,b, CSF:plasma irisin levels correlation in controls (N = 26) (a) or AD patients (b) (N = 14; lines represent linear regression fits to the data; r2 and P values as indicated in the figure). c, CSF to plasma irisin ratio is selectively reduced in AD patients, as compared to controls, MCI or LBD patients (N = 26 controls, 14 MCI, 11 AD, 13 LBD cases). Data are shown as mean ± s.e.m., *P < 0.05; One-way ANOVA with Holm-Sidak post-test.

Extended Data Fig. 3 AβOs reduce FNDC5/irisin levels in hippocampal neurons.

a–c, Primary cultured hippocampal neurons were exposed to 500 nM AβOs for 24 h. Fndc5 mRNA (a) and FNDC5/irisin protein levels (b,c) in cultured hippocampal neurons exposed or not to AβOs (N = 4 experiments with independent neuronal cultures and AβO preparations; data are shown as mean ± s.e.m., **P < 0.01; paired Student’s t-test; two-sided). See Source Data 5 for original data. d,e, Colocalization of surface FNDC5 immunoreactivity (green) with β–tubulin III (red) immunoreactivity in cultured hippocampal neurons (d). Colocalization of surface FNDC5 immunoreactivity (green) with glial fibrillary acidic protein (GFAP) (red) (e). The experiment was repeated 2 times with similar results in independent cultures. f,g, Primary cultured hippocampal neurons were exposed to 500 nM AβOs for 24 h. g, Summary quantification of surface FNDC5 immunoreactivity in cultured neurons (N = 4 experiments with independent neuronal cultures and AβO preparations; 30 images (from 2–3 coverlips) per condition per experiment. Data are shown as mean ± s.e.m. * P < 0.05, paired Student’s t-test; two-sided). h, Surface FNDC5 immunoreactivity (red) in 18 DIV cultured hippocampal neurons after lentiviral knockdown of FNDC5 (shFNDC5) (N = 2 experiments with independent cultures; 30 images (from 2–3 coverslips) per condition per experiment). Scale bar = 10 mm.

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Extended Data Fig. 4 AβOs reduce hippocampal FNDC5, PGC-1α, and PPARγ expression.

a, Hippocampal, cortical, and skeletal muscle (gastrocnemius) expression of FNDC5 in C57BL/6 mice (N = 6 per group). Data are shown as mean ± s.e.m.; *P < 0.05; paired one-way ANOVA with Holm-Sidak correction; two-sided. b,c, Hippocampal FNDC5 mRNA in C57BL/6 i.c.v-infused with 10 pmol AβOs for 24 h (N = 8 per group) (b) or 7 days (N = 5 per group) (c). Data are shown as mean ± s.e.m.; *P < 0.05; Student’s t-test; two-sided). d,e, Skeletal muscle (gastrocnemius) FNDC5 mRNA in C57BL/6 i.c.v-infused with 10 pmol AβOs for 24 h (N = 7 Veh, 5 AβOs) (d) or 7 days (N = 7 Veh, 4 AβOs) (e). Data are shown as mean ± s.e.m.; *P < 0.05; Student’s t-test; two-sided). f–k, Hippocampal mRNA levels of PGC-1α (f,h), PPARγ (g,i) and PPARα (j,k) were measured 24 h or 7 days after infusion, as indicated (N = 5 per group). mRNA levels were normalized by β-actin expression. (l,m) AβOs reduced hippocampal PGC-1α protein levels in C57BL/6 mice 7 days after infusion (N = 7 Veh, 6 AβOs). Data are shown as mean ± s.e.m.; *P < 0.05; Student’s t-test; two-sided). See Source Data 6 for original data.

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Extended Data Fig. 5 Lentiviral vectors expressing shFNDC5 did not cause motor impairment or affect body weight gain in mice.

a,b, Distance traveled (a) and mean velocity (b) of mice allowed to explore an open field arena for 5 min (N = 9 mice for shCtrl, 10 mice each for shFNDC5 (1) and (2) groups). Data are shown as mean ± s.e.m. c, Body weight measured 0, 14 or 28 days after lentiviral injections (N = 10 mice per group; one-way ANOVA followed by Holm-Sidak post-test). Data are shown as mean ± s.e.m. No significantly statistical difference was found among groups.

Extended Data Fig. 6 Intrahippocampal administration of recombinant irisin prevents AβO-induced memory impairment.

a,b, Male Swiss mice (3 months old) were bilaterally injected with recombinant irisin (75 pmol per hippocampus) and received 10 pmol AβOs i.c.v. Novel object recognition (a) and contextual fear conditioning (b) tasks (tested 5 days post-infusion of AβOs) (N = 9 mice for Veh, 10 for AβOs, 9 for irisin and 7 for AβOs + irisin). Data are shown as mean ± s.e.m. *P < 0.05, two-way ANOVA with Holm-Sidak post-test; two-sided.

Extended Data Fig. 7 Validation of PCR array results by qPCR.

a–f, AdFNDC5 expression of 6 synapse plasticity-related genes after AβO injection: Egr1 (a), Egr4 (b), Gria2 (c), Grm2 (d), Nptx2 (e), and Ppp3ca (f). N = 6 mice per experimental group. Data are shown as mean ± s.e.m. *P < 0.05; two-way ANOVA with Holm-Sidak post-test; two-sided.

Extended Data Fig. 8 FNDC5/irisin rescues defective synaptic plasticity and memory in APP/PS1 M146L mice.

a–d, APP/PS1 M146L mice (or WT littermates) were injected i.c.v. with an adenoviral vector expressing full-length FNDC5 (AdFNDC5) or green fluorescent protein (AdGFP, used as a control). Hippocampal slices were obtained and subjected to high-frequency stimulation for LTP recordings. Field excitatory postsynaptic potentials (fEPSP) in hippocampal slices from each experimental group (N = 9 slices for vehicle AdGFP, 7 for APP/PS1 M146L AdGFP, 8 for WT AdFNDC5, 7 for APP/PS1 M146L AdFNDC5; from 3–4 animals per group) (a). fEPSP at 120 min (b). I.c.v.-injected AdFNDC5 rescued memory impairment in 3–4 months-old APP/PS1 M146L mice in 2-day radial arm water maze (c) and in contextual fear conditioning (d) (N = 10 mice for WT GFP, 8 for APP/PS1 GFP, 11 for WT FNDC5, 10 for APP/PS1 FNDC5). Data are shown as mean ± s.e.m. *P < 0.05; two-way ANOVA with Holm-Sidak post-test; two-sided.

Extended Data Fig. 9 Irisin counteracts AD-linked activation of cellular stress response and dendritic spine loss in hippocampal neurons.

a, Effect of irisin on AβO-induced increases in eIF2α-P (green) and upregulation of nuclear ATF4 (red). Nuclei were counterstained in blue (DAPI). Scale bar = 5 mm. b,c, Summary quantification of immunocytochemistry experiments (N = 4 experiments with independent neuronal cultures and AβO preparations). *P < 0.05; two-way ANOVA with Holm-Sidak correction; two-sided. Data are represented by mean ± s.e.m. d,e, Summary quantification of of protein synthesis in hippocampal neurons, as measured by non-radioactive puromycin incorporation (SUnSET) normalized by β-actin levels (N = 4 experiments with independent hippocampal cultures and AβO preparations). *P < 0.05; two-way ANOVA with Holm-Sidak correction; two-sided. Data are represented by mean ± s.e.m. f,g, Representative images of dendritic spines in hippocampal neurons, as measured by F-actin labeling with Alexa-conjugated phalloidin (N = 5 experiments with independent neuronal cultures and AβO preparations). Scale bar = 20 mm. *P < 0.05, two-way ANOVA. Data are shown as mean ± s.e.m. At least 30 neurons were analyzed per condition per experiment in immunocytochemistry experiments. h, AβO binding to cultured hippocampal neurons, as detected by AβO-sensitive antibody NU4 (red), after treatment with recombinant irisin (25 nM). Scale bar, = 10 mm. The experiments were repeated 5 times with similar results. i, Summary quantification of 5 experiments with independent neuronal cultures and AβO preparations. Data are shown as mean ± s.e.m. *P < 0.05; paired one-way ANOVA; two-sided. j, AβO interaction with different proteins in a plate-binding assay. BSA was used as a negative control, while neuroligin-1 was used as a positive control (N = 3 experiments with independent AβO preparations)68. Representative dots were cropped from the same film. See Source Data 7 for original data. k, Double immunocytochemistry colocalization between AβOs (red) and surface FNDC5 (green) in primary cultured hippocampal neurons (3 experiments with independent neuronal cultures and AβO preparations, with 20–25 images (from 2–3 coverslips) per experiment). Scale bar = 5 mm. The experiments were repeated 3 times with similar results. l–o, Levels of soluble (l,n) and insoluble Aβ42 (m,o) in hippocampus (N = 3 for AdGFP, 5 for AdFNDC5) and cortex (N = 3 for AdGFP, 4 for AdFNDC5) of APP/PS1 M146L mice. Data are shown as mean ± s.e.m. *P < 0.05; Student’s t-test; two-sided.

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Extended Data Fig. 10 Exercise blocks AβO-induced memory impairment in mice.

Effect of exercise (swimming; 5 weeks, 5 days/week, 1 h/day) on memory impairment induced by i.c.v. infusion of AβOs in Swiss mice. a–c, Novel object recognition assessed 24 h (N = 9 mice for vehicle, 8 for AβOs, 8 for exercise, 9 for exercise + AβOs) (a) or 5 days post-infusion of AβOs (N = 8 mice for vehicle, 10 for AβOs, 8 for exercise and 8 for exercise + AβOs) (b). Data are shown as mean ± s.e.m. *P < 0.05; one-sample Student’s t-test. Contextual fear conditioning (c) assessed 7 days post-infusion of AβOs (N = 7 mice for vehicle, 8 for AβOs, 9 for exercised and 6 for exercised + AβOs). *P > 0.05; two-way ANOVA followed by Holm-Sidak post-test; two-sided). d,e, Hippocampal FNDC5 mRNA (d) (N = 9 mice per group) and FNDC5/irisin protein levels (e; measured by ELISA) after 5 weeks of exercise (N = 6 mice each for vehicle, AβOs and exercise + AβOs, and 5 for exercise) in male Swiss mice that received 10 pmol AβOs i.c.v. f,g, Hippocampal BDNF levels in exercised mice (N = 10 mice for vehicle and AβOs, 11 for exercise, 13 for exercise + AβOs). Data are shown as mean ± s.e.m. *P < 0.05; **P < 0.01, two-way ANOVA followed by Holm-Sidak post-test; two-sided. Representative bands were cropped from the same membrane. See Source Data 8 for original data.

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Supplementary information

Supplementary Information

Supplementary Tables 1 and 2, describing patient demographics and PCR primer sequences.

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Mass spectrometry data for the corresponding figure.

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Lourenco, M.V., Frozza, R.L., de Freitas, G.B. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med 25, 165–175 (2019). https://doi.org/10.1038/s41591-018-0275-4

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