Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
Taipei Cancer Center, TMU Research Center of Cancer Translational Medicine, Taipei Medical University Hospital, College of Medicine, Taipei Medical University, No. 252, Wuxing St., Xinyi Dist., Taipei, 110301, Taiwan (R.O.C.).
J Biomed Sci. 2024 May 9;31(1):46. doi: 10.1186/s12929-024-01037-2.
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 Ca flux. Once CTSS was suppressed, elevated levels of anti-inflammatory cytokines and changes of Ca influx were observed. These findings have inspired us to explore the potential role of CTSS on cognitive functions.
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.
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.
Our findings suggest a critical role of CTSS in the regulation of cognitive function by modulating the Ca influx, leading to enhanced activation of the BDNF/TrkB axis. Our study may provide a novel strategy for improving cognitive function by targeting CTSS.
组织蛋白酶 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样化的作用。在细胞水平上，CTSS 水平的升高与促炎细胞因子的分泌有关，并破坏了 Ca 流的动态平衡。一旦 CTSS 被抑制，就会观察到抗炎细胞因子水平的升高和 Ca 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 Barnes 迷宫测试，以评估 Ctss 小鼠、Ctss 小鼠和 Ctss 小鼠注射 CTSS 抑制剂（RJW-58）后的空间和工作记忆。对实验动物获得的脑切片进行了长时程增强（LTP）、高尔基染色、免疫荧光染色等离体分析。此外，还使用培养的 HT-22 细胞系和经 RJW-58 处理的原代皮质神经元进行了分子研究，以全面评估基因和蛋白表达。
我们的研究结果表明，靶向组织蛋白酶 S（CTSS）可改善认知功能，提高行为模型中的工作记忆和空间记忆。离体研究表明，LTP 水平升高，突触复杂性增加。微阵列分析表明，当使用 siRNA 敲低 CTSS 时，脑源性神经营养因子（BDNF）的表达上调。此外，CTSS 酶活性的药理学阻断以剂量和时间依赖的方式促进了 BDNF 的表达。值得注意的是，CTSS 的抑制与小鼠齿状回中的神经发生增加有关。这些结果表明 CTSS 调节在认知增强和神经发生中的作用具有广阔的前景。
我们的研究结果表明，CTSS 通过调节 Ca 流入在调节认知功能方面发挥着关键作用，从而增强了 BDNF/TrkB 轴的激活。我们的研究为通过靶向 CTSS 改善认知功能提供了一种新策略。
