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Cited by 403Neurogenesis and neuroplasticity mechanismsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Exercise hormone irisin is a critical regulator of cognitive function

Open access
Islam, Mohammad R., Valaris, Sophia, Young, Michael F., Haley, Erin B., Luo, Renhao, Bond, Sabrina F., Mazuera, Sofia, Kitchen, Robert R. +14 more·2021·Nature Metabolism
DOI 10.1038/s42255-021-00438-zPMC PMC10317538
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Abstract

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD. Irisin is shown to mediate beneficial effects on cognitive function associated with exercise and to improve cognitive function in mouse models of Alzheimer’s disease, probably through its direct action in the brain.

AI snapshot

Written from the paper’s full text.

TL;DR

Irisin, the cleaved circulating form of exercise-induced FNDC5, is sufficient to mediate exercise-related cognitive benefits, and its genetic deletion impairs cognition in exercise, aging, and Alzheimer’s disease models. Peripheral irisin delivery raises central irisin, crosses the blood-brain barrier, and rescues cognitive deficits and neuropathology in two AD mouse models.

Key findings

  • Global FNDC5/irisin knockout (F5KO) mice failed to show exercise-induced improvements in Morris water maze reversal and probe retention, and aged F5KO mice (21–24 months) showed no novel-object preference, unlike aged WT.
  • F5KO mice had impaired pattern separation in contextual fear conditioning discrimination learning, which was rescued by stereotaxic irisin delivery into the dentate gyrus; at 60 min post-HFS, LTP was reduced by 37% compared to WT.
  • Adult-born dentate gyrus neurons in F5KO mice were morphologically, transcriptionally, and functionally abnormal: 459 genes were differentially expressed between F5KO and WT newborn neurons, and irisin co-localized with αVβ5 integrins in 16% [5, 23] of molecules versus 0.4% [0.1, 0.5] with αVβ3.
  • Peripheral AAV8-irisin delivery in APP/PS1 and 5xFAD AD mice improved spatial learning/memory and reduced glial activation; human MSSM RNA-seq data (2,114 samples from 1,234 subjects) showed significantly lower FNDC5 expression in AD parahippocampal gyrus but not other brain regions.

Methods

  • Mouse genetics and models: global F5KO mice generated by crossing Fndc5fl/fl with EIIa-cre; F5KO crossed with APP/PS1 and Thy1-GFP lines; 5xFAD mice used; mice underwent voluntary wheel running, aging cohorts, behavioral testing (MWM, NOR, CFC-DL, Barnes maze, OPF, SAB), electrophysiology, BrdU/EdU labeling, and stereotaxic or tail-vein AAV8 delivery.
  • Newborn-neuron transcriptomics: retroviral GFP-reporter driven by synapsin promoter labeled newborn neuron nuclei, followed by FACS sorting and RNA-seq, yielding 200–500 immature neuron nuclei per mouse; bulk RNA-seq was also performed on microdissected dentate gyrus and AD mouse hippocampus.
  • Binding and human data: two-color dSTORM assessed irisin-FLAG co-localization with αVβ3/αVβ5 integrins in differentiated adult hippocampal neural stem cells; human FNDC5 differential expression came from the MSSM RNA-sequencing study across four brain regions.

Limitations

  • The paper states that it cannot determine whether muscle- or hippocampus-derived irisin mediates exercise benefits, and that tissue-specific KO models will be needed; embryonic F5KO deletion may also cause developmental defects.
  • The paper notes that AD transgenic models are based on familial AD mutations, though it argues irisin’s effects may generalize because irisin targets neuroinflammation rather than amyloid plaques; more mechanistic studies are required to confirm αVβ5 integrin involvement.
  • The text makes evident that commercial irisin ELISA/EIAs measured the same plasma “irisin” concentration in F5KO and WT mice, indicating sensitivity/specificity issues, and that nuclear RNA-seq variability may have left the exercise-effect analysis underpowered.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s42255-021-00438-z

Cites

128 of 128 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 15 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    F5KO mice have reduced maintenance of LTP in the DG compared with WT mice, with LTP 37% lower at 60 min after HFS.

    “At 60 min post-HFS, LTP was reduced by 37% compared to WT (Fig. 1f–i).”
    • Also stated in: § Irisin deletion impairs cognitive function in exercise and aging · plain
      “F5KO mice were not able to sustain LTP as well as the WT mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    F5KO mice do not show the exercise-induced improvement in spatial learning and memory that WT mice show.

    “F5KO mice failed to show the exercise-induced improvements in spatial learning and memory seen in WT mice.”
    • Also stated in: § Irisin deletion impairs cognitive function in exercise and aging · plain
      “Running shortened latency in WT mice but not F5KO mice during the MWM reversal phase (Fig. 1b).”
    • Also stated in: § Irisin deletion impairs cognitive function in exercise and aging · plain
      “WT-run had better spatial memory retention in the 24hr probe trial than their sedentary control group, but F5KO-run did not (Fig. 1c).”
    Quote in the paperSubstantial claim
  • Findingown data

    Basic synaptic transmission and presynaptic transmitter release are equivalent between F5KO and WT mice, based on no differences in fEPSP input/output curves and paired pulse ratio.

    “No significant differences in fEPSP evoked for Input/Output curves and the paired pulse ratio indicate that basic synaptic transmission and presynaptic transmitter release are equivalent (Extended Data Fig. 1s, t).”
    Quote in the paperSubstantial claim
  • Findingown data

    Loss of FNDC5/irisin in global knockout mice worsens cognition across exercise, aging, and Alzheimer's disease.

    “Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD.”
    • Also stated in: § INTRODUCTION · plain
      “Here, we show that genetic deletion of FNDC5/irisin impairs cognitive function in exercise, aging, and AD, in part by alterations of adult newborn neurons in the hippocampus.”
    • Also stated in: § Discussion · boosted
      “We demonstrate that genetic deletion of FNDC5/irisin impairs cognitive function in exercise, aging, and AD.”
    Quote in the paperSubstantial claim
  • Findingown data

    After exercise, F5KO mice have more cFos+/BrdU+/NeuN+ cells (adult-born neurons) in the dorsal hippocampus than WT mice.

    “Interestingly, we found significantly more cFos+/BrdU+/NeuN+ cells (representing adult-born neurons in the DG) in dorsal hippocampal sections from F5KO compared to WT mice (Fig. 3a, c).”
    Quote in the paperSubstantial claim
  • May combine two claims. 23
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Findingown data

    Aged F5KO mice (21-24 months) show greater cognitive decline than aged WT mice, with no preference for the novel object in NOR.

    “However, aged F5KO (21–24 months old) had more cognitive decline than aged WT, showing no preference towards the novel object (Fig. 1e, Extended Data Fig. 1o).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The commercial ELISA/EIA kits measured the same irisin concentration in plasma of F5KO and WT mice, indicating sensitivity or specificity issues.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Lourenco, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the dorsal hippocampus, newborn neuron spine density is lower in F5KO than WT mice and remains lower with exercise.

    “In the dorsal hippocampus, the spine density of newborn neurons was significantly less in F5KO compared to WT mice and this deficit persisted with exercise (Fig. 4g, h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Irisin treatment of APP/PS1 mice improves context discrimination/pattern separation in CFC-DL with similar contexts but does not change performance in CFC with distinct contexts.

    “In line with our data from the global F5KO mice, irisin treatment of APP/PS1 mice improved context discrimination/pattern separation in the CFC-DL with similar contexts but did not change performance in a CFC assay with distinct context (Extended Data Fig. 6k,l and 7k, l).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In CFC-DL with similar contexts, WT mice discriminated as early as day 2, whereas F5KO mice only learned the task by day 6.

    “While WT mice successfully discriminated between contexts as early as day 2, the F5KO only learned this task at day 6 (Fig. 2a).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Liver-derived circulating irisin-FLAG has the expected size of ~12 kDa and is glycosylated like native irisin.

    “Of note, this liver-derived circulating irisin-FLAG had the expected size of ~12kDa and is glycosylated as native irisin (Extended Data Fig. 10a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Running exercise increases dendritic complexity and total dendritic length of newborn neurons in WT mice but not in F5KO mice.

    “Sholl analysis for dendritic complexity and total dendritic length demonstrated that dendritic arbors grew with running exercise in WT mice, as expected, but not in F5KO mice (Fig. 4b–f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    FNDC5 expression is significantly lower in the parahippocampal gyrus of AD patients than controls, but not in other brain regions.

    “Analysis of RNA-seq data from the MSSM study (Mount Sinai School of Medicine, and Mayo), comprising 2,114 samples from 1,234 human subjects, showed significantly lower FNDC5 expression in the parahippocampal gyrus in patients with AD compared to controls, but not in other brain regions (Fig. 6b) 53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Wan, Y.-W. et al. Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 32, 107908 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    APP/PS1-F5KO mice have higher cortical soluble Aβ−40 levels than APP/PS1-WT mice, with no such difference in hippocampus.

    “Interestingly, in the cortex, APP/PS1-F5KO showed significantly higher levels of soluble Aβ−40, which contributes to plaque formation and more dysfunctional vascular integrity 54,55, compared to APP/PS1-WT However, the hippocampus did not present such differences (Extended Data Fig. 5a, b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [54] Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid β-peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007). source

      Not checked in the free run.

    • cites [55] Stakos, D. A. et al. The Alzheimer’s disease amyloid-beta hypothesis in cardiovascular aging and disease: JACC Focus Seminar. J. Am. Coll. Cardiol. 75, 952–967 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the ventral hippocampus, irisin deletion has much less effect on newborn neuron dendritic spine density and no significant effect on spine head size.

    “In the ventral hippocampus, there was much less effect on dendritic spine density and no significant effect on spine head size (Extended Data Fig. 3f–h).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    The authors developed a novel method to profile the transcriptional program of newborn neurons by labeling their nuclei with a GFP-reporter retrovirus driven by a synapsin promoter and then FACS-sorting the nuclei for RNA-sequencing.

    “Here, we have developed a novel approach to ascertain the transcriptional program of newborn neurons by selectively labeling the nuclei of newborn neurons using a GFP-reporter retrovirus driven by a synapsin-promotor (RV-SYN-GTRgp) followed by FACS-sorting isolated nuclei for next-gen RNA-sequencing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Significantly elevated irisin protein levels are detected in the brain but not in the quadriceps after peripheral AAV8-irisin delivery.

    “Notably, we also detected significantly elevated irisin protein levels within the brain but not in the quadriceps (Fig. 8c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only 0.4% [0.1, 0.5] of irisin molecules co-localize with αVβ3 integrins, whereas 16% [5, 23] co-localize with αVβ5 integrins.

    “Clus-DoC analysis on the localization maps with nano-meter scale resolution revealed that only 0.4 % [0.1, 0.5] of irisin molecules were co-localized with αVβ3 integrins whereas significantly more irisin molecules, namely 16% [5, 23], were co-localized with αVβ5 integrins (Fig. 7e, f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Irisin treatment does not change BrdU+ cell number or hippocampal or cortical Aβ-plaque burden.

    “Notably, no differences were detected in the number of BrdU+ cells and hippocampal or cortical Aβ-plaque burden (Extended Data Fig. 8c–h).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Peripheral AAV8-irisin-FLAG injection in 8-month-old APP/PS1 mice overexpresses irisin in the liver and raises circulating irisin to pharmacological levels without overexpressing it in the hippocampus.

    “To evaluate the therapeutic potential of peripherally delivered irisin, 8-month-old male APP/PS1 mice received AAV8-irisin-FLAG or AAV8-GFP via tail vein injections to overexpress irisin in the liver and increase circulating irisin to pharmacological levels (Fig. 6d, e; Extended Data Fig. 6a).”
    • Also stated in: § Peripheral irisin improves cognitive function in AD models · plain
      “Importantly, this resulted not in overexpression in the hippocampus (Extended Data Fig. 6b and 7b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    F5KO and WT mice show no differences in anxiety- or depression-like behavior in elevated plus maze and tail suspension test.

    “To rule out a more anxious disposition as bias, we tested for anxiety- and depression-like behavior using the elevated plus maze and the tail suspension test, detecting no differences between genotypes (Extended Data Fig. 2a, b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Irisin may exert its effects through astrocytes and/or microglia.

    “Our data on reduced glia activation with irisin treatment in AD mouse models suggest that irisin may exert its effects through astrocytes and/or microglia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In CFC-DL, presentation order was counterbalanced to avoid order as a confounder.

    “To avoid presentation order becoming a confounder, half the mice in each group were presented first with context A and then with B, and the other half was presented first with context B, then A.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    F5KO mice show no significant differences from WT in rotarod, grip strength, treadmill gait, or open field in young mice, indicating no confounding motor deficiencies.

    “To ensure no confounding (loco-)motor deficiencies, F5KO underwent rotarod, grip strength, treadmill gait analyses, and the open field test (OPF). We observed no significant differences between genotypes in young mice (Extended Data Fig. 1f–i).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Irisin itself confers the cognitive benefits, as shown by using an AAV8 vector that forces expression of irisin but not the parent protein FNDC5.

    “We demonstrate unequivocally that irisin itself confers the cognitive benefits by employing an AAV8 vector that only forces expression of irisin but not the parent protein FNDC5.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The study used 5xFAD mice to avoid genotype bias and confirm generalization of irisin's effects.

    “To avoid genotype bias and confirm the generalization of irisin’s effects, we also used transgenic AD mouse model, namely 5×FAD mice 56, with AAV8-irisin in the same manner as the APP/PS1 mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Oakley, H. et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal procedures were approved by the Institutional Animal Care and Use Committee of MGH and Harvard Center for Comparative Medicine.

    “All animal procedures were approved by the Institutional Animal Care and Use Committee of the Massachusetts General Hospital (MGH) and the Harvard Center for Comparative Medicine.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Experiments used sex- and age-matched littermates of the indicated genotypes.

    “Experiments were performed with sex- and age-matched littermates of the indicated genotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Aged F5KO and WT mice show no significant differences in bodyweight, open field, or spontaneous alternation behavior.

    “No significant differences in bodyweight, OPF, or SAB were observed between genotypes in aged mice (Extended Data Fig. 1p–r).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In murine DG single-cell RNA-seq data, Itgav is expressed ubiquitously in neuronal and non-neuronal cells, while Itgb5 is mainly expressed on astrocytes and microglia.

    “Single-cell RNA-seq data from the murine DG59 showed that Itgav is expressed ubiquitously in neuronal and non-neuronal cells, whereas Itgb5 is mainly expressed on astrocytes and microglia (Extended Data Fig. 9b, c).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Hochgerner, H., Zeisel, A., Lonnerberg, P. & Linnarsson, S. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing. Nat. Neurosci. 21, 290–299 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Irisin does not specifically target the formation or removal of amyloid plaques but targets neuroinflammation directly.

    “However, since irisin does not specifically target the formation or removal of amyloid plaques, but rather targets neuroinflammation directly, we are optimistic that irisin’s beneficial effects in neurodegeneration are generalizable beyond FAD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    In the NOR, mice that spent less than 10 sec interacting with the objects were excluded because low exploratory activity biases the analysis.

    “In the NOR, mice that spend less than 10 sec interacting with the objects were excluded since low exploratory activity biases the analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Outliers were identified using the Grubbs' test with a two-sided significance level of p<0.05.

    “Outliers were identified using the Grubbs’ test with a significance level of p<0.05 (two-sided).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Operators were blinded to the true experimental groups during data collection and image analysis by de-identifying all samples with generic unique IDs.

    “Operators were blinded to the true experimental groups during data collection and image analysis by de-identifying all samples with generic unique IDs.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    For behavioral tests, exclusion criteria were pre-established following published guidance.

    “For behavioral tests, exclusion criteria were pre-established following published guidance 71,79,80.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [71] Wolf, A., Bauer, B., Abner, E. L., Ashkenazy-Frolinger, T. & Hartz, A. M. A comprehensive behavioral test battery to assess learning and memory in 129S6/Tg2576 mice. PLoS ONE 11, e0147733 (2016). source

      Not checked in the free run.

    • cites [79] Bilsland, J. G. et al. Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacology 33, 685–700 (2008). source

      Not checked in the free run.

    • cites [80] Kim, W. B. & Cho, J.-H. Encoding of contextual fear memory in hippocampal–amygdala circuit. Nat. Commun. 11, 1382 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The study's sample size was chosen based on previously published studies using similar methods.

    “Samples size was based on previously published studies using similar methodologies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants.

    “Significance was assigned only if time spent in the target quadrant was significantly different from all other quadrants (l)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    In the CFC, mice that did not freeze after receiving the shocks on day 1 were excluded from that analysis because freezing cannot be used as a proxy for learning or memory in those mice.

    “In the CFC, mice that did not freeze after receiving the shocks on day 1 were excluded from that analysis as we cannot use freezing as a proxy for learning or memory.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    In the SAB, mice with fewer than 8 arm entries during the 5-min trial were excluded from analysis because lower exploratory activity biases the analysis.

    “In the SAB, mice with less than 8 arm entries during the 5-min trial were excluded from the analysis as significantly lower exploratory activity biases the analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For all experiments, all stated replicates are biological replicates.

    “For all experiments, all stated replicates are biological replicates.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    The embryonic deletion of FNDC5/irisin in F5KO mice does not produce developmental or compensatory effects that account for the cognitive phenotypes.

    “Since FNDC5/irisin was deleted embryonically, it is possible there are development defects in the F5KO mice.”

  • The paper relies on this without support.

    The novel object recognition task depends on multiple brain regions including the hippocampus.

    “The NOR relies on multiple brain regions, including the hippocampus.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Irisin administration in a mouse model of Alzheimer disease improves synaptic plasticity and memory function.

    “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 [156]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Different exons are specified for the Fndc5 knockout

    Major

    The Results state that the targeting construct deletes exons 3 and 4, while the Methods describe the targeted mice as involving exons 2 and 3. These are different descriptions of the knockout used throughout the study.

1 of 1

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Related

Authors
Islam, M. R., Valaris, S., Young, M. F., Haley, E. B., Luo, R., Bond, S. F., Mazuera, S., Kitchen, R. R., Caldarone, B. J., Bettio, L. E. B., Christie, B. R., Schmider, A. B., Soberman, R. J., Besnard, A., Jedrychowski, M. P., Kim, H., Tu, H., Kim, E., Choi, S. H., Tanzi, R. E., Spiegelman, B. M., & Wrann, C. D.
Affiliations
  • Harvard University (US)
  • Northeastern University (US)
  • Brigham and Women's Hospital (US)
  • University of Victoria (CA)
  • LakePharma (United States) (US)
Corresponding author
Wrann, Christiane D.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2021-08-20
Volume
3
Issue
8
Pages
1058-1070
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-021-00438-z
PMC
PMC10317538
OpenAlex
W3194164206
Semantic Scholar
71d5d79e877143d4f8ab7ffb66cfd5acc4705b08
Cited by
403
References
128
Citations by year
2026: 73 · 2025: 87 · 2024: 85 · 2023: 98 · 2022: 55 · 2021: 4
FWCI
22.13
Type
journal article
Language
en
Update notices
correction (2021-10-07)
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • FRAXA Research Foundation
  • Harvard NeuroDiscovery Center
  • University of Pennsylvania
  • Cure Alzheimer's Fund
  • Michael Smith Health Research BC
  • Scheme for Promotion of Academic and Research Collaboration
  • National Institutes of Health (P30NS04776)
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council of Canada
  • National Institute on Aging (R56AG064580, R21AG062904)
  • National Cancer Institute (R01CA193520)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062472, K01DK089145)
  • National Institute of Neurological Disorders and Stroke (R00NS087096, P30NS04776, K99NS087096, P30NS045776, R01NS117694)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR065538)
  • National Center for Research Resources (S10RR027931)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
irisin, FNDC5, physical activity, cognitive function, Alzheimer's disease, aging, pattern separation, dentate gyrus, adult neurogenesis, adeno-associated virus, cognitive decline, neuroprotection
MeSH terms
Animals, Behavior, Animal, Cognition, Cognition Disorders, Disease Models, Animal, Fibronectins, Hormones, Phenotype, Physical Conditioning, Animal, Gene Expression, Gene Deletion, Mice, Knockout, Mice

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