靶向 cathepsin S 可促进 OLF1-BDNF/TrkB 轴的激活,从而增强认知功能。

IF 9 2区 医学 Q1 CELL BIOLOGY
Hao-Wei Lee, Szu-Jung Chen, Kuen-Jer Tsai, Kuei-Sen Hsu, Yi-Fan Chen, Chih-Hua Chang, Hsiao-Han Lin, Wen-Yun Hsueh, Hsing-Pang Hsieh, Yueh-Feng Lee, Huai-Chueh Chiang, Jang-Yang Chang
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引用次数: 0

摘要

背景:Cathepsin S(CTSS)是一种半胱氨酸蛋白酶,在免疫、肿瘤转移、衰老和其他病理改变中发挥着多种作用。在细胞水平上,CTSS 水平的升高与促炎细胞因子的分泌和 Ca2+ 通量平衡的破坏有关。一旦 CTSS 被抑制,就会观察到抗炎细胞因子水平的升高和 Ca2+ 流入的变化。这些发现启发我们探索 CTSS 对认知功能的潜在作用:我们进行了经典的Y迷宫和巴恩斯迷宫测试,以评估Ctss-/-小鼠、Ctss+/+小鼠和注射了CTSS抑制剂(RJW-58)的Ctss+/+小鼠的空间记忆和工作记忆。对实验动物的全脑组织切片进行了体内外分析,包括长期延时(LTP)、高尔基体染色和免疫荧光染色。此外,还使用培养的 HT-22 细胞系和经 RJW-58 处理的原代皮层神经元进行了分子研究,以全面评估基因和蛋白质的表达:我们的研究结果表明,靶向 cathepsin S(CTSS)可改善认知功能,增强行为模型中的工作记忆和空间记忆。体内外研究显示,长期延时水平升高,突触复杂性增加。微阵列分析表明,使用 siRNA 敲除 CTSS 后,脑源性神经营养因子(BDNF)上调。此外,药物阻断 CTSS 酶活性能以剂量和时间依赖的方式促进 BDNF 的表达。值得注意的是,抑制 CTSS 与小鼠齿状回神经发生的增加有关。这些结果表明,CTSS调节在认知增强和神经发生中具有重要作用:我们的研究结果表明,通过调节 Ca2+ 流入,CTSS 在认知功能调控中发挥了关键作用,从而增强了 BDNF/TrkB 轴的激活。我们的研究可能为通过靶向 CTSS 改善认知功能提供了一种新策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function.

Background: Cathepsin S (CTSS) is a cysteine protease that played diverse roles in immunity, tumor metastasis, aging and other pathological alterations. At the cellular level, increased CTSS levels have been associated with the secretion of pro-inflammatory cytokines and disrupted the homeostasis of Ca2+ flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca2+ influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions.

Methods: We conducted classic Y-maze and Barnes Maze tests to assess the spatial and working memory of Ctss-/- mice, Ctss+/+ mice and Ctss+/+ mice injected with the CTSS inhibitor (RJW-58). Ex vivo analyses including long-term potentiation (LTP), Golgi staining, immunofluorescence staining of sectioned whole brain tissues obtained from experimental animals were conducted. Furthermore, molecular studies were carried out using cultured HT-22 cell line and primary cortical neurons that treated with RJW-58 to comprehensively assess the gene and protein expressions.

Results: Our findings reported that targeting cathepsin S (CTSS) yields improvements in cognitive function, enhancing both working and spatial memory in behavior models. Ex vivo studies showed elevated levels of long-term potentiation levels and increased synaptic complexity. Microarray analysis demonstrated that brain-derived neurotrophic factor (BDNF) was upregulated when CTSS was knocked down by using siRNA. Moreover, the pharmacological blockade of the CTSS enzymatic activity promoted BDNF expression in a dose- and time-dependent manner. Notably, the inhibition of CTSS was associated with increased neurogenesis in the murine dentate gyrus. These results suggested a promising role of CTSS modulation in cognitive enhancement and neurogenesis.

Conclusion: Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca2+ influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.

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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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