{"title":"Exercise-induced irisin ameliorates cognitive impairment following chronic cerebral hypoperfusion by suppressing neuroinflammation and hippocampal neuronal apoptosis.","authors":"Weiping Xiao, Yibing Yang, Lu Bai, Peixuan Yang, Runze Li, Daizhi Yang, Fanying Li, Lingzhi Quan, Qiupeng Liang, Yan Yan, Tiewei Qi, Feng Liang","doi":"10.1186/s12974-025-03493-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"168"},"PeriodicalIF":10.1000,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12205520/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neuroinflammation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12974-025-03493-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes.
Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems.
The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.