Exercise-induced irisin ameliorates cognitive impairment following chronic cerebral hypoperfusion by suppressing neuroinflammation and hippocampal neuronal apoptosis.

Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2004-

Fibronectins*/metabolism ; Hippocampus*/metabolism ; Hippocampus*/pathology ; Apoptosis*/physiology ; Cognitive Dysfunction*/etiology ; Cognitive Dysfunction*/metabolism ; Cognitive Dysfunction*/therapy ; Cognitive Dysfunction*/pathology ; Physical Conditioning, Animal*/physiology ; Physical Conditioning, Animal*/methods ; Neurons*/metabolism ; Neurons*/pathology ; Neuroinflammatory Diseases*/metabolism ; Neuroinflammatory Diseases*/pathology ; Neuroinflammatory Diseases*/etiology; Animals ; Male ; Mice ; Mice, Inbred C57BL

Background: Chronic cerebral hypoperfusion (CCH) is a pathophysiological hallmark of vascular dementia, the second most common form of dementia. CCH exerts complex and subtle detrimental effects on both the brain and peripheral systems. Irisin is a polypeptide primarily expressed in contracting skeletal muscle and the brain. However, its role in CCH remains unclear. This study aimed to investigate the effects of CCH on irisin metabolism and whether increasing endogenous irisin levels through forced aerobic exercise (FAE) could confer neuroprotection against secondary brain injury induced by CCH.
Methods: A total of 212 adult (8-week-old) male C57BL/6 mice were randomly assigned to either sham or CCH groups. CCH was induced by bilateral common carotid artery stenosis. FAE consisted of daily swimming (1 h/day, 5 days/week, for 5 weeks). Two subgroups of CCH mice received daily intraperitoneal injections of either DMSO or cilengitide trifluoroacetate (CT), a selective inhibitor of integrin αV and β5 (the irisin receptor), during FAE. ELISA and western blotting were used to assess irisin expression, while western blotting, TUNEL, immunofluorescence staining, and neurobehavioral tests were conducted to evaluate neurofunctional outcomes.
Results: Hippocampal and serum irisin levels were progressively reduced in CCH mice. Additionally, expression of integrins αV and β5 in hippocampal neurons, microglia, and astrocytes decreased post-CCH. FAE effectively enhanced both peripheral and central irisin expression. Increased endogenous irisin levels inhibited CCH-induced hippocampal neuronal apoptosis and microglial activation, thereby promoting neuronal survival and partially ameliorating white matter injury. These changes led to improvements in memory, motor function, and anxiety- and depression-like behaviors. Mechanistically, the neuroprotective effects of irisin were mediated by enhanced hippocampal neuronal and microglial autophagy through increased AMPK phosphorylation and decreased mTOR phosphorylation-effects abolished by CT treatment.
Conclusion: Our findings demonstrate that enhancing endogenous irisin via FAE mitigates CCH-induced neuronal apoptosis, microglial activation, cognitive impairment, and affective behavioral deficits by promoting autophagy through the integrin αVβ5/AMPK/mTOR signaling pathway.
(© 2025. The Author(s).)

Declarations. Ethics approval and consent to participate: All experiments described in this study were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Sun Yat-sen University (China), and carried out according to the Regulations for Laboratory Animal Management by the Ministry of Science and Technology of the People’s Republic of China. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Nat Cell Biol. 2011 Mar;13(3):263-72. (PMID: 21336308)
J Cell Mol Med. 2020 Jan;24(1):996-1009. (PMID: 31701659)
Dement Geriatr Cogn Disord. 2008;26(3):270-6. (PMID: 18841012)
Front Neurol. 2021 Sep 13;12:755046. (PMID: 34589052)
Ann Neurol. 2024 Jul;96(1):61-73. (PMID: 38780366)
Cell Metab. 2015 Oct 6;22(4):734-740. (PMID: 26278051)
Nat Metab. 2021 Aug;3(8):1058-1070. (PMID: 34417591)
Acta Neuropathol. 2024 Aug 5;148(1):15. (PMID: 39102080)
Int Immunopharmacol. 2025 Mar 06;149:114201. (PMID: 39914281)
Biol Sex Differ. 2017 Feb 9;8:7. (PMID: 28203366)
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1713-8. (PMID: 22307636)
Mol Psychiatry. 2021 Aug;26(8):4544-4560. (PMID: 33299135)
Exp Mol Med. 2022 Jul;54(7):1038-1048. (PMID: 35882943)
Neurobiol Aging. 2017 Sep;57:153-161. (PMID: 28648916)
Nature. 2012 Jan 11;481(7382):463-8. (PMID: 22237023)
J Neuroinflammation. 2023 May 3;20(1):105. (PMID: 37138312)
Ageing Res Rev. 2017 Nov;40:51-63. (PMID: 28903070)
Neuron. 2025 Jan 8;113(1):29-48. (PMID: 39406236)
Lancet. 2013 Jun 8;381(9882):2016-23. (PMID: 23746902)
Cell. 2018 Dec 13;175(7):1756-1768.e17. (PMID: 30550785)
Mol Cell. 2008 Apr 25;30(2):214-26. (PMID: 18439900)
Autophagy. 2024 Mar;20(3):590-613. (PMID: 37908119)
Science. 2024 May 3;384(6695):563-572. (PMID: 38696572)
Adv Sci (Weinh). 2025 Jan;12(1):e2403818. (PMID: 39467260)
Cell Death Dis. 2022 Mar 30;13(3):283. (PMID: 35354793)
Sci Rep. 2017 Feb 27;7:43296. (PMID: 28240298)
Mol Cell Biol. 2009 Jul;29(14):3991-4001. (PMID: 19451232)
Cell Death Dis. 2016 Feb 18;7:e2101. (PMID: 26890140)
J Neuroinflammation. 2021 Aug 28;18(1):187. (PMID: 34454529)
JCI Insight. 2023 Aug 22;8(16):. (PMID: 37606039)
J Cell Physiol. 2019 Aug;234(10):17578-17588. (PMID: 30793300)
Neurology. 2010 Oct 19;75(16):1415-22. (PMID: 20944075)
Cell Mol Neurobiol. 2015 Jan;35(1):101-10. (PMID: 25352419)
Life Sci. 2024 Nov 15;357:123088. (PMID: 39357796)
NPJ Parkinsons Dis. 2025 Mar 23;11(1):55. (PMID: 40122927)
J Pineal Res. 2019 Mar;66(2):e12542. (PMID: 30516280)
Brain. 2017 Nov 1;140(11):3023-3038. (PMID: 29053824)
Science. 2019 May 31;364(6443):825-826. (PMID: 31147505)
Br J Sports Med. 2022 Jun;56(12):701-709. (PMID: 35301183)
Neuropeptides. 2015 Aug;52:47-54. (PMID: 26142757)
Neuropsychopharmacology. 2018 Dec;43(13):2627-2635. (PMID: 29487370)
Am J Physiol Endocrinol Metab. 2014 Mar 1;306(5):E512-8. (PMID: 24398403)
Neuropharmacology. 2024 Aug 1;253:109986. (PMID: 38705569)
Biomed Res Int. 2014;2014:908915. (PMID: 25089278)
Stroke. 2025 Mar;56(3):758-776. (PMID: 39545328)
Autophagy. 2024 Jan;20(1):4-14. (PMID: 37594406)
Aging Dis. 2021 Aug 1;12(5):1197-1210. (PMID: 34341702)
Autophagy. 2024 Apr;20(4):847-862. (PMID: 37915255)
Proc Natl Acad Sci U S A. 2015 Aug 4;112(31):9745-50. (PMID: 26195764)
Neuroimage. 2016 May 1;131:81-90. (PMID: 26477656)
Brain Behav Immun. 2025 Mar;125:68-91. (PMID: 39701329)
JCI Insight. 2020 Jul 9;5(13):. (PMID: 32516137)
Autophagy. 2024 Feb;20(2):221-241. (PMID: 37700498)
J Neuroinflammation. 2022 Apr 7;19(1):82. (PMID: 35392928)
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8):. (PMID: 33593893)
Nat Commun. 2024 Jan 9;15(1):383. (PMID: 38195627)
Lancet Neurol. 2022 Oct;21(10):889-898. (PMID: 36115361)
Nat Med. 2019 Jan;25(1):165-175. (PMID: 30617325)
J Neuroeng Rehabil. 2025 Feb 28;22(1):42. (PMID: 40022168)
Gene. 2002 Sep 4;297(1-2):79-83. (PMID: 12384288)
Cell. 2019 Jul 11;178(2):507-508. (PMID: 31299203)
Front Aging Neurosci. 2021 Apr 16;13:649929. (PMID: 33935687)
Autophagy. 2021 Nov;17(11):3813-3832. (PMID: 33404280)
Drug Resist Updat. 2025 Jan;78:101170. (PMID: 39603146)
Aging (Albany NY). 2021 Feb 3;13(7):9522-9541. (PMID: 33539323)
Mol Neurobiol. 2017 Jul;54(5):3670-3682. (PMID: 27206432)
Alzheimers Dement. 2023 Jun;19(6):2595-2604. (PMID: 36465055)
Cell Metab. 2013 Nov 5;18(5):649-59. (PMID: 24120943)
Brain Pathol. 2018 Jan;28(1):3-13. (PMID: 28703923)
Microbiome. 2022 Apr 17;10(1):62. (PMID: 35430804)
Front Aging Neurosci. 2020 Apr 28;12:104. (PMID: 32410981)
J Hazard Mater. 2025 May 05;488:137310. (PMID: 39862777)
Neurochem Res. 2018 Aug;43(8):1549-1560. (PMID: 29882126)
Cell. 2003 Nov 26;115(5):577-90. (PMID: 14651849)
Metabolism. 2017 Mar;68:31-42. (PMID: 28183451)
EBioMedicine. 2016 Apr;6:139-148. (PMID: 27211556)
Alzheimers Dement. 2022 Nov;18(11):2023-2035. (PMID: 34994517)
Genes Dev. 2003 Aug 1;17(15):1829-34. (PMID: 12869586)
J Clin Invest. 2015 Jan;125(1):25-32. (PMID: 25654547)
Theranostics. 2020 Jan 1;10(1):74-90. (PMID: 31903107)
Lancet Neurol. 2019 Nov;18(11):998-1008. (PMID: 31521532)
Cytokine. 2019 Oct;122:154303. (PMID: 29472066)
Front Aging Neurosci. 2021 Feb 03;13:640215. (PMID: 33613273)
Mediators Inflamm. 2018 Sep 26;2018:9070341. (PMID: 30356412)
Neuron. 2013 Nov 20;80(4):844-66. (PMID: 24267647)
J Neuroinflammation. 2018 May 2;15(1):133. (PMID: 29720216)
Nat Rev Neurol. 2018 Jul;14(7):387-398. (PMID: 29802354)
Theranostics. 2018 Aug 10;8(16):4535-4551. (PMID: 30214637)
Neurology. 2011 Jul 19;77(3):288-94. (PMID: 21768599)
FASEB J. 2023 Oct;37(10):e23175. (PMID: 37742293)
Ageing Res Rev. 2024 Sep;100:102463. (PMID: 39179115)
Redox Biol. 2018 May;15:335-346. (PMID: 29306791)
Dev Dyn. 2002 Jun;224(2):154-67. (PMID: 12112469)
J Inflamm Res. 2023 Mar 11;16:1045-1057. (PMID: 36936349)
Mol Neurobiol. 2025 Jul;62(7):8843-8856. (PMID: 40048058)
Ageing Res Rev. 2023 Dec;92:102127. (PMID: 37979700)
Exp Neurol. 2022 Dec;358:114225. (PMID: 36100045)
Neurology. 2000;54(11 Suppl 5):S4-9. (PMID: 10854354)
Neurotherapeutics. 2018 Oct;15(4):1158-1167. (PMID: 30030698)

No. 82301459 National Natural Science Foundation of China; No. 81902524 National Natural Science Foundation of China; No. 82302924 National Natural Science Foundation of China; 2022M723646 China Postdoctoral Science Foundation; 2023A04J2216 Guangzhou Science and Technology Program; No. 2022A1515110129 to F. L. Basic and Applied Basic Research Foundation of Guangdong Province; YSTTGDPMAA202502 Young Science and Technology Talent Support Program of Guangdong Precision Medicine Application Association

Keywords: Aerobic exercise; Chronic cerebral hypoperfusion; Irisin; Neuroinflammation; Neuronal apoptosis

0 (Fibronectins)
0 (FNDC5 protein, mouse)

Date Created: 20250628 Date Completed: 20250628 Latest Revision: 20250703

20260130

PMC12205520

10.1186/s12974-025-03493-5

40581647