鸢尾素通过TFAM介导的线粒体新陈代谢抑制小鼠脑干胶质细胞衰老。

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Cailin Wang, Xiufeng Wang, Shangqi Sun, Yanmin Chang, Piaopiao Lian, Hongxiu Guo, Siyi Zheng, Rong Ma, Gang Li
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引用次数: 0

摘要

背景:衰老小胶质细胞的积累已被强调为导致陶陶病进展的一个关键因素。鸢尾素是一种肌肉源性荷尔蒙,由含有纤连蛋白-结构域III的5(FNDC5)蛋白水解产生,它介导了运动对身体的多重效应。在此,我们研究了鸢尾素在tauopathies小胶质细胞衰老中的潜在作用:为了在体内和体外模拟tau病,我们分别利用了P301S tau转基因小鼠和tau K18纤维处理的小胶质细胞BV2。我们首先研究了tau病中小胶质细胞的鸢尾素表达和衰老表型。随后,我们研究了鸢尾素对小胶质细胞衰老的影响及其潜在的分子机制:结果:我们在体内和体外都观察到了鸢尾素水平的降低和小胶质细胞过早衰老的开始。结果:我们在体内和体外都观察到了鸢尾素水平的降低和小胶质细胞过早衰老的发生,并发现鸢尾素能抵消小胶质细胞的衰老并改善 P301S 小鼠的认知能力下降。从机理上讲,鸢尾素通过刺激线粒体转录因子 A(线粒体呼吸链生物生成的主调节因子)的表达,从而增强线粒体氧化磷酸化(OXPHOS),有效抑制了小胶质细胞的衰老。沉默 TFAM 可消除鸢尾素对小胶质细胞衰老的抑制作用以及鸢尾素对线粒体氧化磷酸化的恢复作用。此外,SIRT1/PGC1α信号通路似乎与鸢尾素介导的TFAM上调有关:综上所述,我们的研究揭示了鸢尾素通过TFAM驱动的线粒体生物生成减轻了小胶质细胞的衰老,这为针对tauopathies的治疗策略提供了一条很有前景的新途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

Background: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies.

Methods: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms.

Result: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM.

Conclusion: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
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