Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MA, Abisambra JF, Tovar-Moll F, Mattos P, Arancio O, Ferreira ST, De Felice FG. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019 Jan;25(1):165-175. Epub 2019 Jan 7 PubMed.

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  1. Irisin, an exercise factor or a protein fragment of the biologically active FNDC5 protein?

    Lourenco et al. postulate that aspects of hormonal signaling, and insulin in particular, are defective in Alzheimer’s disease (AD) and hence there is scope for the protein FNDC5, or more specifically a fragment of that protein, to play a role in cognitive function given its potential role in metabolism in mice. There is no direct human clinical data that CNS ”insulin resistance” is a causal factor for AD, as rates of emergence of diabetes (or not) and numbers of emerging cases of AD in the Framingham or Baltimore Age studies (Thambisetty  et al., 2013; Akomolafe et al., 2015) are unrelated. This is an example of epidemiological co-association—an issue that plagues modern medicine. So it is rather strange that Lourenco et al. make this their central clinical hypothesis.

    FNDC5 has only consistently acted as an exercise factor according to data from Bruce Spiegelman’s lab at Massachusetts General Hospital, but their original Nature publication was first-authored by a scientist found to have carried out scientific fraud with respect to RNA measurements, while working at a previous institution, and it was also unclear RNA measurements which caught our attention when inspecting the original irisin article (Timmons et al., 2012; Atherton and Phillips, 2013). The largest human studies, using hundreds of subjects, have reported that the FNDC5 gene is not activated by exercise—directly challenging the original hypothesis that FNDC5 is a PGC1α-activated canonical mediator. Studies in mice have tended to report a more consistent metabolic action for FNDC5, albeit with many caveats, suggesting responses in the mouse may be distinct. So can we expect exercise to “activate” FNDC5 and produce “irisin” (if it exists in humans)?

    What is not in doubt is that the original irisin work did not measure the proposed “irisin” peptide/protein as the antibody did not work (Albrecht et al., 2015). Lack of clarity over this point required a second study from Spiegelman’s laboratory, fast-tracked in Cell Metabolism. The article first of all reported detection of the irisin peptide in human samples using a new assay (at levels that could be non-specific degradation of FNDC5 protein), and this new assay is still of unknown validity because the work has never been independently followed up.

    The second claim in this article was that they could detect greater levels of the irisin protein in samples taken from people who had undergone exercise training. The clinical samples came from a co-author’s lab, Dr. Nair, and were used in a very strange manner. The original clinical study was a much larger study and had samples from control (no exercise) and exercise-trained subjects, both before and at the end of the study period. However only four control samples were compared with six post-training samples when measuring “irisin,” i.e., many of the study samples were not used and the normal, more robust paired analysis was not presented (same person, samples before and after). The values of “irisin” greatly overlapped between control and exercise subgroups. Dr. Spiegelman has been offered access to much larger clinical cohorts by our group, but has not taken up those offers.

    To claim that there is robust or definitive evidence, as the authors did, that irisin was exercise-regulated is not terribly scientific and no robust follow-up of this pilot work has been produced. Notably, an initial $50 million venture capital investment in a company formed around this project has not continued. Critically, the new article by Lourenco et al. therefore incorrectly claims that the presence of the cleaved FNDC5 product in plasma was “settled” by Spiegelman’s group.

    Links between FNDC5 and BDNF, a protein proven to have important functions in the CNS, also originate from the Spiegelman lab. In this new murine study by Lourenco et al., they link exercise, FNDC5 gene activation, and cognitive function (and neurochemical markers of neuronal function). They very clearly report substantial changes in these markers in the face of manipulating the levels of FNDC5. However, their stated approach to measuring the “active” component of FNDC5 is by their own admission flawed—it does not distinguish between FNDC5 and the fabled exercise factor, Irisin. i.e.

    “Moreover, irisin has been reported to exhibit an apparent molecular mass in the 22–32 kDa range resulting from dimerization and/or glycosylation15,18–21. This is similar to the molecular mass of FNDC516,21, making it difficult to discriminate between FNDC5 and irisin in immunoblots from tissue samples where both FNDC5 and irisin may be present. Thus, in the current study, we refer to FNDC5/irisin when describing results based on immunological detection of irisin in brain tissue homogenates. On the other hand, because irisin is thought to comprise the majority of secreted FNDC5/irisin16, we refer to irisin when describing results obtained in CSF or plasma using an irisin enzyme-linked immunosorbent assay (ELISA) kit.”

    It is simply not scientifically robust to say that most FNDC5 detected in blood/plasma should be irisin, so we will call the results we get irisin.

    Examination of the human data in this largely preclinical study, indicates a very small sample size, so small, as evidenced by Figure 1e, that there is actually no genuine relationship between FNDC5 protein (mislabeled as “irisin”) and human AD brain status. The vast majority of this very small dataset has values in the same range—while ~five late-stage AD have low values—presumably reflective of more severe atrophy or gross histological changes, and not at all to do with specific loss of the membrane protein FNDC5. The plasma data indicates no relationship with AD, while the use of correlation analysis is inappropriate given the sample size (Gobbi and Jurman, 2015; Schönbrodt and Perugini, 2013). CSF data are also not very robust—the range of values is similar in the small disease group as it is in the larger control group—but none of the datasets are of a meaningful size for a human clinical study, where accurate determinations of representative group values only really stabilize with hundreds of samples or more.

    While these authors may well be observing that FNDC5, a membrane-related protein, somehow impacts on cognitive status of the mouse when artificially overexpressed or removed, i.e., large non-physiological shifts in this membrane protein, it would be curious if an important exercise factor, produced a “positive gain” when overexpressed constantly, 24 hours a day, given that any health benefits from exercise tend to reflect relatively short periods (10 minutes to a few hours) of physical activity per week (Phillips et al., 2017). Most of the other murine data is of little direct relevance to human AD, human exercise, or the proposed link between them.

    References:

    Thambisetty M, Jeffrey Metter E, Yang A, Dolan H, Marano C, Zonderman AB, Troncoso JC, Zhou Y, Wong DF, Ferrucci L, Egan J, Resnick SM, O'Brien RJ. Glucose intolerance, insulin resistance, and pathological features of Alzheimer disease in the Baltimore Longitudinal Study of Aging. JAMA Neurol. 2013 Sep 1;70(9):1167-72. PubMed.

    Akomolafe A, Beiser A, Meigs JB, Au R, Green RC, Farrer LA, Wolf PA, Seshadri S. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol. 2006 Nov;63(11):1551-5. PubMed.

    Atherton PJ, Phillips BE. Greek goddess or Greek myth: the effects of exercise on irisin/FNDC5 in humans. J Physiol. 2013 Nov 1;591(21):5267-8. PubMed.

    Albrecht E, Norheim F, Thiede B, Holen T, Ohashi T, Schering L, Lee S, Brenmoehl J, Thomas S, Drevon CA, Erickson HP, Maak S. Irisin - a myth rather than an exercise-inducible myokine. Sci Rep. 2015 Mar 9;5:8889. PubMed.

    Timmons JA, Baar K, Davidsen PK, Atherton PJ. Is irisin a human exercise gene?. Nature. 2012 Aug 30;488(7413):E9-10; discussion E10-1. PubMed.

    Gobbi A, Jurman G. A null model for Pearson coexpression networks. PLoS One. 2015;10(6):e0128115. Epub 2015 Jun 1 PubMed.

    Schönbrodt FD, Perugini M. At what sample size do correlations stabilize?. J Res Pers. 2013;47(5):609-612.

    Phillips BE, Kelly BM, Lilja M, Ponce-González JG, Brogan RJ, Morris DL, Gustafsson T, Kraus WE, Atherton PJ, Vollaard NB, Rooyackers O, Timmons JA. A Practical and Time-Efficient High-Intensity Interval Training Program Modifies Cardio-Metabolic Risk Factors in Adults with Risk Factors for Type II Diabetes. Front Endocrinol (Lausanne). 2017;8:229. Epub 2017 Sep 8 PubMed.

    View all comments by James Timmons

  2. This detailed study of irisin as a positive modulator of synaptic plasticity and as a peptide that can ameliorate the neurotoxicity of synthetic Aβ oligomers in hippocampal slice cultures and in mouse models of AD in vivo appears quite compelling. The concept that exercise can mitigate some of the effects of Aβ oligomers has been seen in several previous studies, and the current work on the beneficial effects of irisin may help explain the reproducible benefits of exercise in AD and mouse models thereof. We have studied combinations of exercise and environmental novelty (see, e.g., Li et al., 2013; Xu et al., 2016) and have found that both approaches—separately or together—can lessen the negative neuronal and microglial effects of natural Aβ oligomers isolated from AD brains. It would now be interesting to see if these benefits also include protective effects of irisin.

    References:

    Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, Selkoe DJ. Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers. Neuron. 2013 Mar 6;77(5):929-41. PubMed.

    Xu H, Gelyana E, Rajsombath M, Yang T, Li S, Selkoe D. Environmental Enrichment Potently Prevents Microglia-Mediated Neuroinflammation by Human Amyloid β-Protein Oligomers. J Neurosci. 2016 Aug 31;36(35):9041-56. PubMed.

    View all comments by Dennis Selkoe

  3. BDNF is a known mediator of cognitive function; its levels are increased by exercise and decreased in AD. The exercise-induced myokine FNDC5/irisin has been shown to induce BDNF levels in brain (Wrann et al., 2013). Now this important and thorough study from the De Felice lab adds significantly to our understanding of how FNDC5/irisin contributes to exercise-induced cognitive function. The paper identifies FNDC5/irisin deficits in AD and demonstrates rescue of cognitive deficits in Alzheimer’s model mice, thereby introducing irisin as a potential therapeutic for Alzheimer’s disease.

    A major advance of this study is the use of FNDC5/irisin to rescue memory deficits in two different mouse models of Alzheimer’s disease (APP/PS1ΔE9 and i.c.v. oligomeric Aβ injection). FNDC5/irisin rescued hippocampal LTP, novel object recognition (NOR), and contextual fear conditioning (CFC) deficits in AD mice. FNDC5/irisin knockdown reduced LTP and performance in NOR, but curiously, not in CFC or radial arm water maze. The reasons for these differences between memory tests are not clear.

    Both brain and peripheral expression of FNDC5/irisin rescued Aβ-induced deficits, suggesting that peripheral FNDC5/irisin can cross the BBB. Importantly, brain or peripheral reduction of FNDC5/irisin prevented exercise-induced rescue of Aβ-induced LTP and NOR deficits, highlighting the importance of peripheral as well as central FNDC6/irisin for exercise-induced cognitive benefits. Although peripheral FNDC5/irisin increased brain FNDC5/irisin protein levels, brain mRNA was not tested, which would help answer the question of whether it crosses the BBB to induce BDNF or triggers expression of endogenous brain FNDC5/irisin.

    The study also provides evidence for a proposed mechanism for FNDC5/irisin induction of BDNF via the cAMP-PKA-CREB pathway. Although the authors demonstrate that PKA inhibition blocks irisin-induced CREB phosphorylation, they stop short of determining whether PKA inhibition abolishes irisin-induced memory rescue. As the authors point out, the irisin receptor and its downstream signaling pathways in both the brain and the periphery are unknown, which is a major goal for future research.

    The roles and mechanisms of peripheral vs. central FNDC5/irisin are still unclear, but this paper provides solid support for the importance of FNDC5/irisin in the maintenance of synaptic plasticity and memory.  The paper provides clear evidence that FNDC5/irisin levels are reduced in AD brain tissue and CSF but not plasma, and that FNDC5/irisin may be used to rescue synaptic plasticity and memory. This should stimulate further studies using FNDC5/irisin as a therapeutic for cognitive deficits in AD.

    References:

    Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway. Cell Metab. 2013 Oct 8; PubMed.

    View all comments by Margaret Fahnestock

  4. This study greatly supports the concept that growth factors have beneficial effects in AD. BDNF, NGF, IGF-1 and other growth factors have shown good neuroprotective effects in neurodegenerative disorders. This study adds another candidate to the list, irisin. Let's hope this will be translational and help AD patients.

    View all comments by Christian Holscher

  5. A number of recent studies have demonstrated roles of FNDC5/irisin in several tissues other than the brain, including adipose tissue (Lee et al., 2014; Zhang et al., 2014), bone (Colaianni et al., 2015; Zhang et al., 2017; Kim et al., 2018), and lung (Chen et al., 2017).

    It was not the aim of our study to perform a large clinical investigation of FNDC5/irisin in humans, but rather to provide initial clinical relevance to the findings obtained in mice. Nonetheless, calculation of statistical power, taking into account the observed effect sizes, revealed sufficient power to detect the correlations we report. We agree it will be important to see our current results extended to additional, possibly larger cohorts. We hope our initial findings may encourage further studies of this potentially relevant avenue for investigation of AD mechanisms.

    References:

    Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, Lu P, Sartini L, Di Comite M, Mori G, Di Benedetto A, Brunetti G, Yuen T, Sun L, Reseland JE, Colucci S, New MI, Zaidi M, Cinti S, Grano M. The myokine irisin increases cortical bone mass. Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):12157-62. Epub 2015 Sep 15 PubMed.

    Chen K, Xu Z, Liu Y, Wang Z, Li Y, Xu X, Chen C, Xia T, Liao Q, Yao Y, Zeng C, He D, Yang Y, Tan T, Yi J, Zhou J, Zhu H, Ma J, Zeng C. Irisin protects mitochondria function during pulmonary ischemia/reperfusion injury. Sci Transl Med. 2017 Nov 29;9(418) PubMed.

    Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, Zhou C, Chou J, Parkman VA, Novick SJ, Strutzenberg TS, Pascal BD, Le PT, Brooks DJ, Roche AM, Gerber KK, Mattheis L, Chen W, Tu H, Bouxsein ML, Griffin PR, Baron R, Rosen CJ, Bonewald LF, Spiegelman BM. Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell. 2018 Dec 13;175(7):1756-1768.e17. PubMed.

    Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014 Feb 4;19(2):302-9. PubMed.

    Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MA, Abisambra JF, Tovar-Moll F, Mattos P, Arancio O, Ferreira ST, De Felice FG. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019 Jan;25(1):165-175. Epub 2019 Jan 7 PubMed.

    Zhang J, Valverde P, Zhu X, Murray D, Wu Y, Yu L, Jiang H, Dard MM, Huang J, Xu Z, Tu Q, Chen J. Exercise-induced irisin in bone and systemic irisin administration reveal new regulatory mechanisms of bone metabolism. Bone Res. 2017;5:16056. Epub 2017 Feb 21 PubMed.

    Zhang Y, Li R, Meng Y, Li S, Donelan W, Zhao Y, Qi L, Zhang M, Wang X, Cui T, Yang LJ, Tang D. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes. 2014 Feb;63(2):514-25. Epub 2013 Oct 22 PubMed.

    View all comments by Fernanda De Felice

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