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

IF 10.1 1区 医学 Q1 IMMUNOLOGY
Weiping Xiao, Yibing Yang, Lu Bai, Peixuan Yang, Runze Li, Daizhi Yang, Fanying Li, Lingzhi Quan, Qiupeng Liang, Yan Yan, Tiewei Qi, Feng Liang
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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.

运动诱导的鸢尾素通过抑制神经炎症和海马神经元凋亡改善慢性脑灌注不足后的认知障碍。
背景:慢性脑灌注不足(CCH)是血管性痴呆的病理生理标志,血管性痴呆是第二常见的痴呆形式。CCH对大脑和外周系统都有复杂而微妙的有害影响。鸢尾素是一种主要在收缩骨骼肌和大脑中表达的多肽。然而,其在CCH中的作用尚不清楚。本研究旨在探讨CCH对鸢尾素代谢的影响,以及通过强制有氧运动(FAE)增加内源性鸢尾素水平是否能对CCH诱导的继发性脑损伤提供神经保护。方法:212只成年雄性(8周龄)C57BL/6小鼠随机分为假手术组和CCH组。双侧颈总动脉狭窄引起CCH。FAE包括每日游泳(1小时/天,5天/周,共5周)。两个亚组的CCH小鼠在FAE期间每天接受DMSO或西伦吉肽三氟乙酸(CT)腹腔注射,CT是一种选择性整合素αV和β5(鸢尾素受体)的抑制剂。ELISA和western blotting检测鸢尾素表达,western blotting、TUNEL、免疫荧光染色和神经行为学检测检测神经功能。结果:CCH小鼠海马和血清中鸢尾素水平逐渐降低。此外,cch后海马神经元、小胶质细胞和星形胶质细胞中整合素αV和β5的表达减少。FAE有效地增强了周围和中央鸢尾素的表达。内源性鸢尾素水平升高可抑制cch诱导的海马神经元凋亡和小胶质细胞活化,从而促进神经元存活,部分改善白质损伤。这些变化导致了记忆力、运动功能以及类似焦虑和抑郁的行为的改善。从机制上讲,鸢尾素的神经保护作用是通过增强海马神经元和小胶质细胞自噬来介导的,通过增加AMPK磷酸化和降低mTOR磷酸化,而这种作用被CT治疗所消除。结论:我们的研究结果表明,通过FAE增强内源性鸢尾素可通过整合素αVβ5/AMPK/mTOR信号通路促进自噬,从而减轻cch诱导的神经元凋亡、小胶质细胞活化、认知功能障碍和情感行为缺陷。
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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
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.
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