{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T11:14:43Z","timestamp":1789902883272,"version":"4.0.1"},"reference-count":96,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009886","name":"Regione Puglia","doi-asserted-by":"publisher","award":["D.G.R. n. 2117 of 21.11.2018 to Maria Grano and Giancarlo Logroscino"],"award-info":[{"award-number":["D.G.R. n. 2117 of 21.11.2018 to Maria Grano and Giancarlo Logroscino"]}],"id":[{"id":"10.13039\/501100009886","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Irisin, the circulating peptide originating from fibronectin type III domain-containing protein 5 (FNDC5), is mainly expressed by muscle fibers under peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1\u03b1) control during exercise. In addition to several beneficial effects on health, physical activity positively affects nervous system functioning, particularly the hippocampus, resulting in amelioration of cognition impairments. Recently, FNDC5\/irisin detection in hippocampal neurons and the presence of irisin in the cerebrospinal fluid opened a new intriguing chapter in irisin history. Interestingly, in the hippocampus of mice, exercise increases FNDC5 levels and upregulates brain-derived neurotrophic factor (BDNF) expression. BDNF, displaying neuroprotection and anti-inflammatory effects, is mainly produced by microglia and astrocytes. In this review, we discuss how these glial cells can morphologically and functionally switch during neuroinflammation by modulating the expression of a plethora of neuroprotective or neurotoxic factors. We also focus on studies investigating the irisin role in neurodegenerative diseases (ND). The emerging involvement of irisin as a mediator of the multiple positive effects of exercise on the brain needs further studies to better deepen this issue and the potential use in therapeutic approaches for neuroinflammation and ND.<\/jats:p>","DOI":"10.3390\/ijms22041605","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T08:33:48Z","timestamp":1612514028000},"page":"1605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["FNDC5\/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective"],"prefix":"10.3390","volume":"22","author":[{"given":"Patrizia","family":"Pignataro","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy"},{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Dicarlo","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Zerlotin","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zecca","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari, \u201cPia Fondazione Card G. Panico\u201d Hospital Tricase, 73039 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Dell\u2019Abate","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari, \u201cPia Fondazione Card G. Panico\u201d Hospital Tricase, 73039 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Buccoliero","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Logroscino","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy"},{"name":"Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari, \u201cPia Fondazione Card G. Panico\u201d Hospital Tricase, 73039 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Colucci","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-5899","authenticated-orcid":false,"given":"Maria","family":"Grano","sequence":"additional","affiliation":[{"name":"Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature10777","article-title":"A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis","volume":"481","author":"Wu","year":"2012","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/dvdy.10099","article-title":"Mouse PeP: A novel peroxisomal protein linked to myoblast differentiation and development","volume":"224","author":"Chien","year":"2002","journal-title":"Dev. Dyn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0378-1119(02)00828-4","article-title":"Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes","volume":"297","author":"Teufel","year":"2002","journal-title":"Gene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.cmet.2015.08.001","article-title":"Detection and quantitation of circulating human irisin by tandem mass spectrometry","volume":"22","author":"Jedrychowski","year":"2015","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Raschke, S., Elsen, M., Gassenhuber, H., Sommerfeld, M., Schwahn, U., Brockmann, B., Jung, R., Wisl\u00f8ff, U., Tj\u00f8nna, A.E., and Raastad, T. (2013). Evidence against a beneficial effect of irisin in humans. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073680"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8889","DOI":"10.1038\/srep08889","article-title":"Irisin\u2014A myth rather than an exercise- inducible myokine","volume":"5","author":"Albrecht","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.gene.2014.12.010","article-title":"Enhanced expression of FNDC5 in human embryonic stem cell-derived neural cells along with relevant embryonic neural tissues","volume":"557","author":"Ghahrizjani","year":"2015","journal-title":"Gene"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuroscience.2013.02.050","article-title":"Irisin-immunoreactivity in neural and non-neural cells of the rodent","volume":"240","author":"Dun","year":"2013","journal-title":"Neuroscience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29898","DOI":"10.1038\/srep29898","article-title":"FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle","volume":"6","author":"Cordido","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.cmet.2013.09.008","article-title":"Exercise induces hippocampal BDNF through a PGC-1alpha\/FNDC5 pathway","volume":"18","author":"Wrann","year":"2013","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.peptides.2018.03.018","article-title":"An update on the role of irisin in the regulation of endocrine and metabolic functions","volume":"104","author":"Mahgoub","year":"2018","journal-title":"Peptides"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Korta, P., Poche\u0107, E., and Mazur-Bia\u0142y, A. (2019). Irisin as a multifunctional protein: Implications for health and certain diseases. Medicina, 55.","DOI":"10.3390\/medicina55080485"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/s11914-020-00600-8","article-title":"Myokines and osteokines in the pathogenesis of muscle and bone diseases","volume":"18","author":"Colaianni","year":"2020","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.pcad.2019.02.007","article-title":"A role for FNDC5\/Irisin in the beneficial effects of exercise on the brain and in neurodegenerative diseases","volume":"62","author":"Young","year":"2019","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Colaianni, G., Errede, M., Sanesi, L., Notarnicola, A., Celi, M., Zerlotin, R., Storlino, G., Pignataro, P., Oranger, A., and Pesce, V. (2020). Irisin correlates positively with BMD in a cohort of older adult patients and downregulates the senescent marker p21 in osteoblasts. J. Bone Min. Res, online ahead of print.","DOI":"10.1002\/JBMR.4192\/v2\/response1"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E512","DOI":"10.1152\/ajpendo.00308.2013","article-title":"The identification of irisin in human cerebrospinal fluid: Influence of adiposity, metabolic markers, and gestational diabetes","volume":"306","author":"Piya","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.peptides.2018.03.013","article-title":"Detection and quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry","volume":"103","author":"Ruan","year":"2018","journal-title":"Peptides"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.peptides.2019.01.004","article-title":"The effects of both age and sex on irisin levels in paired plasma and cerebrospinal fluid in healthy humans","volume":"113","author":"Ruan","year":"2019","journal-title":"Peptides"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1210\/me.2014-1353","article-title":"Irisin, a novel myokine, regulates glucose uptake in skeletal muscle cells via AMPK","volume":"29","author":"Lee","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.biocel.2016.07.022","article-title":"Irisin ameliorates hepatic glucose\/lipid metabolism and enhances cell survival in insulin-resistant human HepG2 cells through adenosine monophosphate-activated protein kinase signaling","volume":"78","author":"So","year":"2016","journal-title":"Int. J. Biochem. Cell. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/ijo.2015.199","article-title":"Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway","volume":"40","author":"Xin","year":"2016","journal-title":"Int. J. Obes. (Lond.)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"524","DOI":"10.3389\/fendo.2019.00524","article-title":"Irisin: A hope in understanding and managing obesity and metabolic syndrome","volume":"10","author":"Arhire","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12157","DOI":"10.1073\/pnas.1516622112","article-title":"The myokine irisin increases cortical bone mass","volume":"112","author":"Colaianni","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1038\/s41598-017-02557-8","article-title":"Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice","volume":"7","author":"Colaianni","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10096","DOI":"10.1096\/fj.202000216R","article-title":"Irisin prevents microgravity-induced impairment of osteoblast differentiation in vitro during the space flight CRS-14 mission","volume":"34","author":"Colucci","year":"2020","journal-title":"Faseb J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/jbmr.3944","article-title":"Irisin prevents disuse-induced osteocyte apoptosis","volume":"35","author":"Storlino","year":"2020","journal-title":"J. Bone Min. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/j.cell.2018.10.025","article-title":"Irisin mediates effects on bone and fat via alphaV integrin receptors","volume":"175","author":"Kim","year":"2018","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13578-020-00413-3","article-title":"New insights into the cellular activities of Fndc5\/Irisin and its signaling pathways","volume":"10","author":"Rabiee","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.metabol.2013.04.007","article-title":"Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines","volume":"62","author":"Moon","year":"2013","journal-title":"Metabolism"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41591-018-0275-4","article-title":"Exercise-linked FNDC5\/irisin rescues synaptic plasticity and memory defects in Alzheimer\u2019s models","volume":"25","author":"Lourenco","year":"2019","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00424-019-02253-8","article-title":"Roles of myokines in exercise-induced improvement of neuropsychiatric function","volume":"471","author":"Kim","year":"2019","journal-title":"Pflug. Arch"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.tins.2007.06.011","article-title":"Exercise builds brain health: Key roles of growth factor cascades and inflammation","volume":"30","author":"Cotman","year":"2007","journal-title":"Trends Neuro Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.cmet.2012.08.012","article-title":"Energy intake and exercise as determinants of brain health and vulnerability to injury and disease","volume":"16","author":"Mattson","year":"2012","journal-title":"Cell. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.tics.2019.01.006","article-title":"Exercise and Hippocampal Memory Systems","volume":"23","author":"Voss","year":"2019","journal-title":"Trends Cogn. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e45920","DOI":"10.7554\/eLife.45920","article-title":"Exercise-induced enhancement of synaptic function triggered by the inverse BAR protein, Mtss1L","volume":"8","author":"Chatzi","year":"2019","journal-title":"Elife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1503\/cmaj.051351","article-title":"Health benefits of physical activity: The evidence","volume":"174","author":"Warburton","year":"2006","journal-title":"CMAJ"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"99","DOI":"10.31887\/DCNS.2013.15.1\/kerickson","article-title":"Physical activity and brain plasticity in late adulthood","volume":"15","author":"Erickson","year":"2013","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: The devil is in the details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia function in the central nervous system during health and neurodegeneration","volume":"35","author":"Colonna","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_40","first-page":"cer-14-17","article-title":"Microglia: The brain\u2019s first responders","volume":"2017","author":"Bilbo","year":"2017","journal-title":"Cerebrum"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nm.4397","article-title":"Microglia emerge as central players in brain disease","volume":"23","author":"Salter","year":"2017","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.it.2016.06.006","article-title":"Astrocytes: Key regulators of neuroinflammation","volume":"37","author":"Colombo","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.it.2007.01.005","article-title":"Astrocytes are active players in cerebral innate immunity","volume":"28","author":"Farina","year":"2007","journal-title":"Trends Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/nature21029","article-title":"Neurotoxic reactive astrocytes are induced by activated microglia","volume":"541","author":"Liddelow","year":"2017","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/j.it.2020.07.006","article-title":"Microglia and astrocytes in disease: Dynamic duo or partners in crime?","volume":"41","author":"Liddelow","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Mee-inta, O., Zhao, Z.-W., and Kuo, Y.-M. (2019). Physical Exercise Inhibits Inflammation and Microglial Activation. Cells, 8.","DOI":"10.3390\/cells8070691"},{"key":"ref_48","first-page":"6","article-title":"Interleukin-6 in acute exercise and training: What is the biological relevance?","volume":"12","author":"Fischer","year":"2006","journal-title":"Exerc. Immunol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"E433","DOI":"10.1152\/ajpendo.00074.2003","article-title":"IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans","volume":"285","author":"Steensberg","year":"2003","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/S1474-4422(09)70062-6","article-title":"Neuroinflammation in Parkinson\u2019s disease: A target for neuroprotection?","volume":"8","author":"Hirsch","year":"2009","journal-title":"Lancet Neurol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bbamcr.2011.01.034","article-title":"The pro- and anti-inflammatory properties of the cytokine interleukin-6","volume":"1813","author":"Scheller","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1186\/ar1917","article-title":"Interleukin-6 and chronic inflammation","volume":"8","author":"Gabay","year":"2006","journal-title":"Arthritis Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1212\/WNL.0000000000000665","article-title":"Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife","volume":"83","author":"Dugravot","year":"2014","journal-title":"Neurology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1249\/MSS.0b013e31822f94ac","article-title":"Muscular interleukin-6 and its role as an energy sensor","volume":"44","author":"Pedersen","year":"2012","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Dong, Y., Pu, K., Duan, W., Chen, H., Chen, L., and Wang, Y. (2018). Involvement of Akt\/CREB signaling pathways in the protective effect of EPA against interleukin-1beta-induced cytotoxicity and BDNF down-regulation in cultured rat hippocampal neurons. BMC Neurosci., 19.","DOI":"10.1186\/s12868-018-0455-7"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1111\/jnc.13497","article-title":"Regulation of cyclic AMP response element-binding protein during neuroglial interactions","volume":"136","author":"Qin","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1038\/npp.2010.105","article-title":"Is glycogen synthase kinase-3 a central modulator in mood regulation?","volume":"35","author":"Li","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.neuroscience.2012.08.065","article-title":"Glucocorticoid regulation of brain-derived neurotrophic factor: Relevance to hippocampal structural and functional plasticity","volume":"239","author":"Suri","year":"2013","journal-title":"Neuroscience"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1038\/nn.2655","article-title":"The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching","volume":"13","author":"Jeanneteau","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1186\/s12974-015-0362-0","article-title":"Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice","volume":"12","author":"Littlefield","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.metabol.2016.12.003","article-title":"The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1\/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia","volume":"68","author":"Li","year":"2017","journal-title":"Metabolism"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.molimm.2017.09.014","article-title":"Irisin protects against neuronal injury induced by oxygen-glucose deprivation in part depends on the inhibition of ROS-NLRP3 inflammatory signaling pathway","volume":"91","author":"Peng","year":"2017","journal-title":"Mol. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jchemneu.2018.02.010","article-title":"The effect of intrathecal injection of irisin on pain threshold and expression rate of GABAB receptors in peripheral neuropathic pain model","volume":"91","author":"Dameni","year":"2018","journal-title":"J. Chem. Neuroanat."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9070341","DOI":"10.1155\/2018\/9070341","article-title":"Irisin Exerts Neuroprotective Effects on Cultured Neurons by Regulating Astrocytes","volume":"2018","author":"Wang","year":"2018","journal-title":"Mediat. Inflamm"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pesce, M., Ballerini, P., Paolucci, T., Puca, I., Farzaei, M.H., and Patruno, A. (2020). Irisin and Autophagy: First Update. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207587"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Rocchi, A., Yamamoto, S., Ting, T., Fan, Y., Sadleir, K., Wang, Y., Zhang, W., Huang, S., Levine, B., and Vassar, R. (2017). A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer\u2019s disease. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006962"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4474","DOI":"10.18632\/aging.102899","article-title":"Irisin activates Opa1-induced mitophagy to protect cardiomyocytes against apoptosis following myocardial infarction","volume":"12","author":"Xin","year":"2020","journal-title":"Aging (Albany Ny)"},{"key":"ref_68","first-page":"1003","article-title":"Neuroinflammation induces neurodegeneration","volume":"1","author":"Kempuraj","year":"2016","journal-title":"J. Neurol. Neurosurg. Spine"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3389\/fnagi.2016.00126","article-title":"Chronic inflammation links cancer and Parkinson\u2019s disease","volume":"8","author":"Li","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0896-6273(02)00794-8","article-title":"Inflammation in neurodegenerative disease\u2014A double-edged sword","volume":"35","author":"Mucke","year":"2002","journal-title":"Neuron"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.phrs.2018.01.012","article-title":"A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: An introductory review","volume":"129","author":"Askari","year":"2018","journal-title":"Pharm. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"582484","DOI":"10.3389\/fphar.2020.582484","article-title":"Irisin protects against motor dysfunction of rats with spinal cord injury via Adenosine 5\u2032-Monophosphate (AMP)-activated protein kinase-nuclear factor kappa-B pathway","volume":"11","author":"Jiang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3389\/fncel.2015.00191","article-title":"Soluble amyloid-\u03b2 oligomers as synaptotoxins leading to cognitive impairment in Alzheimer\u2019s disease","volume":"9","author":"Ferreira","year":"2015","journal-title":"Frontiers in Cellular Neuroscience"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1126\/science.1074069","article-title":"Alzheimer\u2019s disease is a synaptic failure","volume":"298","author":"Selkoe","year":"2002","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1111\/jnc.13713","article-title":"Synaptopathies: Synaptic dysfunction in neurological disorders","volume":"138","author":"Lepeta","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/325733a0","article-title":"The precursor of Alzheimer\u2019s disease amyloid A4 protein resembles a cell-surface receptor","volume":"325","author":"Kang","year":"1987","journal-title":"Nature"},{"key":"ref_77","first-page":"1366","article-title":"Targeting the neurotoxic species in Alzheimer\u2019s disease: Inhibitors of Abeta oligomerization","volume":"18","author":"Vieira","year":"2004","journal-title":"STFASEB J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.pneurobio.2007.02.001","article-title":"Structure and functions of the human amyloid precursor protein: The whole is more than the sum of its parts","volume":"82","author":"Gralle","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1385\/JMN:23:1-2:105","article-title":"BACE1: The beta-secretase enzyme in Alzheimer\u2019s disease","volume":"23","author":"Vassar","year":"2004","journal-title":"J. Mol. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/ana.10208","article-title":"Increased expression of the amyloid precursor beta-secretase in Alzheimer\u2019s disease","volume":"51","author":"Holsinger","year":"2002","journal-title":"Ann. Neurol"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"29621","DOI":"10.1074\/jbc.R800015200","article-title":"The role of amyloid precursor protein processing by BACE1, the beta-secretase, in Alzheimer disease pathophysiology","volume":"283","author":"Cole","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1186\/s13041-018-0401-8","article-title":"Fibronectin type III domain-containing protein 5 interacts with APP and decreases amyloid \u03b2 production in Alzheimer\u2019s disease","volume":"24","author":"Noda","year":"2018","journal-title":"Mol. Brain"},{"key":"ref_83","first-page":"e12034","article-title":"Cerebrospinal fluid irisin correlates with amyloid-\u03b2, BDNF, and cognition in Alzheimer\u2019s disease","volume":"12","author":"Lourenco","year":"2020","journal-title":"Alzheimers Dement. (Amst)."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.3233\/JAD-170447","article-title":"Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway","volume":"59","author":"Laptinskaya","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Tsai, C.L., and Pai, M.C. (2020). Circulating levels of Irisin in obese individuals at genetic risk for Alzheimer\u2019s disease: Correlations with amyloid-\u03b2, metabolic, and neurocognitive indices. Behav. Brain Res., 113013.","DOI":"10.1016\/j.bbr.2020.113013"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/joim.12190","article-title":"Mild cognitive impairment: A concept in evolution","volume":"275","author":"Petersen","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.jalz.2014.01.001","article-title":"Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer\u2019s disease","volume":"10","author":"Jessen","year":"2014","journal-title":"Alzheimers Dement."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"Contributors. NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimer Dement."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1126\/science.1067389","article-title":"Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson\u2019s disease","volume":"295","author":"Auluck","year":"2002","journal-title":"Science"},{"key":"ref_90","first-page":"722","article-title":"Irisin protects the substantia nigra dopaminergic neurons in the rat model of Parkinson\u2019s disease","volume":"22","author":"Zarbakhsh","year":"2019","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1139\/apnm-2018-0545","article-title":"The effect of preventive exercise on the neuroprotection in 6-hydroxydopamine-lesioned rat brain","volume":"44","author":"Rezaee","year":"2019","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/bs.irn.2019.06.003","article-title":"Exercise and Parkinson\u2019s disease","volume":"147","author":"Xu","year":"2019","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e2157","DOI":"10.1212\/WNL.0000000000008567","article-title":"Physical activity and prodromal features of Parkinson disease","volume":"93","author":"Hughes","year":"2019","journal-title":"Neurology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.3389\/fimmu.2017.01005","article-title":"Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications","volume":"8","author":"Liu","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.nbd.2016.11.001","article-title":"ALS-causing mutations differentially affect PGC-1\u03b1 expression and function in the brain vs. peripheral tissues","volume":"97","author":"Bayer","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3001","DOI":"10.1007\/s00415-018-9093-3","article-title":"Serum irisin is upregulated in patients affected by amyotrophic lateral sclerosis and correlates with functional and metabolic status","volume":"265","author":"Lunetta","year":"2018","journal-title":"J. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1605\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:19:55Z","timestamp":1760159995000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,5]]},"references-count":96,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041605"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041605","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,5]]}}}