Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function

Autor: 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
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Journal of Biomedical Science, Vol 31, Iss 1, Pp 1-23 (2024)
Druh dokumentu: article
ISSN: 1423-0127
60065435
DOI: 10.1186/s12929-024-01037-2
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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