- 作者: 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
- 作者服務機構: 1.Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan 2.Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan 3.Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan 4.Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan 5.Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan 6.Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan 7.Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan 8.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.)
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Cathepsin S, Cognitive function, OLF-1, Brain-derived neurotrophic factor