國家衛生研究院 NHRI:Item 3990099045/15832

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/15832

Title:	Targeting cathepsin S promotes activation of OLF1-BDNF/TrkB axis to enhance cognitive function
Authors:	Lee, HW;Chen, SJ;Tsai, KJ;Hsu, KS;Chen, YF;Chang, CH;Lin, HH;Hsueh, WY;Hsieh, HP;Lee, YF;Chiang, HC;Chang, JY
Contributors:	Institute of Biotechnology and Pharmaceutical Research;Immunology Research Center
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.
Date:	2024-05-09
Relation:	Journal of Biomedical Science. 2024 May 09;31:Article number 46.
Link to:	http://dx.doi.org/10.1186/s12929-024-01037-2
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1021-7770&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:001217362600002
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85192487292
Appears in Collections:	[Jang-Yang Chang] Periodical Articles [Hsing-Pang Hsieh] Periodical Articles [Others] Periodical Articles

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