PDF(Pubmed)
Abstract：
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.
RESULTS: 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.
CONCLUSIONS: 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.
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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：已强调衰老小胶质细胞的积累是tau蛋白病变进展的关键因素。Irisin,一种肌肉衍生的激素，通过蛋白水解裂解含5的纤连蛋白结构域III（FNDC5）产生，介导运动对身体的多效性影响。在这里，我们研究了irisin在tau蛋白病小胶质细胞衰老中的潜在作用。
方法：为了在体内和体外模拟tau蛋白病变，我们利用P301Stau转基因小鼠和tauK18原纤维处理的小胶质细胞BV2，分别。我们首先检查了tau蛋白病中小胶质细胞的irisin表达和衰老表型。随后，我们研究了irisin对小胶质细胞衰老的影响及其潜在的分子机制。
结果：我们在体内和体外观察到irisin水平的降低和小胶质细胞过早衰老的开始。发现Irisin给药可以抵消小胶质细胞衰老并改善P301S小鼠的认知功能下降。机械上,irisin通过刺激线粒体转录因子A(TFAM)的表达,有效抑制小胶质细胞衰老,线粒体呼吸链生物发生的主要调节因子，从而增强线粒体氧化磷酸化(OXPHOS)。沉默TFAM消除了irisin对小胶质细胞衰老的抑制作用以及irisin对线粒体OXPHOS的恢复作用。此外，SIRT1/PGC1α信号通路似乎与irisin介导的TFAM上调有关。
结论：综合来看，我们的研究表明，irisin通过TFAM驱动的线粒体生物发生减轻小胶质细胞衰老，为针对tau蛋白病的治疗策略提供了有希望的新途径。
方法：为了在体内和体外模拟tau蛋白病变，我们利用P301Stau转基因小鼠和tauK18原纤维处理的小胶质细胞BV2，分别。我们首先检查了tau蛋白病中小胶质细胞的irisin表达和衰老表型。随后，我们研究了irisin对小胶质细胞衰老的影响及其潜在的分子机制。
结果：我们在体内和体外观察到irisin水平的降低和小胶质细胞过早衰老的开始。发现Irisin给药可以抵消小胶质细胞衰老并改善P301S小鼠的认知功能下降。机械上,irisin通过刺激线粒体转录因子A(TFAM)的表达,有效抑制小胶质细胞衰老,线粒体呼吸链生物发生的主要调节因子，从而增强线粒体氧化磷酸化(OXPHOS)。沉默TFAM消除了irisin对小胶质细胞衰老的抑制作用以及irisin对线粒体OXPHOS的恢复作用。此外，SIRT1/PGC1α信号通路似乎与irisin介导的TFAM上调有关。
结论：综合来看，我们的研究表明，irisin通过TFAM驱动的线粒体生物发生减轻小胶质细胞衰老，为针对tau蛋白病的治疗策略提供了有希望的新途径。
