{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:58:41Z","timestamp":1781719121594,"version":"3.54.5"},"reference-count":63,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM149348"],"award-info":[{"award-number":["R35 GM149348"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM080532"],"award-info":[{"award-number":["R01 GM080532"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32 GM139789"],"award-info":[{"award-number":["T32 GM139789"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Caspase-6 (casp-6), is a member of the apoptotic family of caspases (cysteine aspartic proteases) and has been shown to be involved in several neurodegenerative diseases, including Alzheimer\u2019s disease. Drug discovery efforts have focused on specific inhibition of casp-6, and it is important that lead compounds demonstrate engagement and inhibition of the protease\n                    <jats:italic>in vivo<\/jats:italic>\n                    . A casp-6 overexpressing mouse model was reported, but is no longer available to the scientific community. We developed alternative means of activating casp-6 in commercially available mice as a platform to test potential casp-6 inhibitors. Lipopolysaccharides (LPS) from\n                    <jats:italic>E. coli<\/jats:italic>\n                    was used to stimulate an immunogenic response in WT C57BL\/6NJ mice, which has been shown to activate the NLRP1 inflammasome, which activates casp-1 and subsequently, casp-6. Key tissues (brain, colon, and thymus) were sampled and evaluated for casp-6 activation by immunoblotting for both active casp-6 and a cleaved lamin A, a casp-6 substrate, and by directly measuring VEIDase activity in tissue lysates. Using in-house bred WT C57BL\/6NJ mice, which had never been subjected to shipping, with a single intraperitoneal dose of LPS (5 mg\/kg) and a 4-hour incubation, we observed robust casp-6 activation in the thymus. We also established VEIDase activity assays as a more reliable marker of casp-6 function than monitoring levels of casp-6 or cleaved substrates, and established the importance of using a non-immunogenic vehicle. We observed casp-6 activation in aged mice as a second useful model, which also further implicates casp-6 in age-related neurodegenerative pathways. These are new means to test the efficacy of casp-6 inhibitors using a simple\n                    <jats:italic>in vivo<\/jats:italic>\n                    assay that can robustly activate casp-6 in an easily accessible laboratory mouse strain. We foresee that these developments will drive drug discovery efforts aimed at identifying casp-6 inhibitors in various disease contexts, including neurodegeneration.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0351312","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:38:17Z","timestamp":1781717897000},"page":"e0351312","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimized detection of caspase-6 activation in a murine inflammation model to inform neurodegenerative disease 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apoptosis","volume":"93","author":"A Takahashi","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"28","key":"pone.0351312.ref009","doi-asserted-by":"crossref","first-page":"16443","DOI":"10.1074\/jbc.271.28.16443","article-title":"The CED-3\/ICE-like protease Mch2 is activated during apoptosis and cleaves the death substrate lamin A","volume":"271","author":"K Orth","year":"1996","journal-title":"J Biol Chem"},{"issue":"2","key":"pone.0351312.ref010","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/sj.cdd.4401753","article-title":"Caspase-1 activation of caspase-6 in human apoptotic neurons","volume":"13","author":"H Guo","year":"2006","journal-title":"Cell Death Differ"},{"issue":"10","key":"pone.0351312.ref011","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1038\/cdd.2015.16","article-title":"Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal 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Yue","year":"2014","journal-title":"Nature"},{"key":"pone.0351312.ref023","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/S0952-7915(99)00046-1","article-title":"Tlr4: central component of the sole mammalian LPS sensor","volume":"12","author":"B Beutler","year":"2000","journal-title":"Curr Opin Immunol"},{"issue":"4","key":"pone.0351312.ref024","first-page":"5463","article-title":"NLRP1 and NLRP3 inflammasomes mediate LPS\/ATP\u2011induced pyroptosis in knee osteoarthritis","volume":"17","author":"L-R Zhao","year":"2018","journal-title":"Mol Med Rep"},{"issue":"15","key":"pone.0351312.ref025","doi-asserted-by":"crossref","first-page":"9677","DOI":"10.1074\/jbc.272.15.9677","article-title":"Substrate specificities of caspase family proteases","volume":"272","author":"RV Talanian","year":"1997","journal-title":"J Biol Chem"},{"issue":"29","key":"pone.0351312.ref026","doi-asserted-by":"crossref","first-page":"17907","DOI":"10.1074\/jbc.272.29.17907","article-title":"A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis","volume":"272","author":"NA Thornberry","year":"1997","journal-title":"J Biol Chem"},{"issue":"135","key":"pone.0351312.ref027","first-page":"57610","article-title":"Injections of lipopolysaccharide into mice to mimic entrance of microbial-derived products after intestinal barrier breach","author":"K Raduolovic","year":"2018","journal-title":"J Vis Exp"},{"key":"pone.0351312.ref028","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3748\/wjg.v11.i3.357","article-title":"Effect of lipopolysaccharide on diarrhea and gastrointestinal transit in mice: roles of nitric oxide and prostaglandin E2","volume":"11","author":"YC Liang","year":"2005","journal-title":"World J Gastroenterol"},{"key":"pone.0351312.ref029","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.physbeh.2007.03.006","article-title":"The palatability of corn oil and linoleic acid to mice as measured by short-term two-bottle choice and licking tests","volume":"91","author":"T Yoneda","year":"2007","journal-title":"Physiol Behav"},{"issue":"6","key":"pone.0351312.ref030","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/10915810600961531","article-title":"Nonclinical vehicle use in studies by multiple routes in multiple species","volume":"25","author":"SC Gad","year":"2006","journal-title":"Int J Toxicol"},{"key":"pone.0351312.ref031","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/toxsci\/kfaa177","article-title":"Differential toxicological outcome of corn oil exposure in rats and mice as assessed by microbial composition, epithelial permeability, and ileal mucosa-associated immune status","volume":"180","author":"K Gokulan","year":"2021","journal-title":"Toxicol Sci"},{"key":"pone.0351312.ref032","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1093\/ilar.47.4.364","article-title":"Establishing an appropriate period of acclimatization following transportation of laboratory animals","volume":"47","author":"JA Obernier","year":"2006","journal-title":"ILAR J"},{"issue":"7","key":"pone.0351312.ref033","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1080\/08820139.2025.2523315","article-title":"Genetic differences between N and J sub-strains of C57BL\/6 mice critically affect multiple immune responses and their microbiota","volume":"54","author":"A Hiergeist","year":"2025","journal-title":"Immunol Invest"},{"key":"pone.0351312.ref034","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.rvsc.2021.01.022","article-title":"Inter-vendor variance of enteric eukaryotic DNA viruses in specific pathogen free C57BL\/6N mice","volume":"136","author":"TS Rasmussen","year":"2021","journal-title":"Res Vet Sci"},{"key":"pone.0351312.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0271651","article-title":"Metabolic differences and differentially expressed genes between C57BL\/6J and C57BL\/6N mice substrains","volume":"17","author":"S Nemoto","year":"2022","journal-title":"PLoS One"},{"issue":"7973","key":"pone.0351312.ref036","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s41586-023-06373-1","article-title":"cGAS-STING drives ageing-related inflammation and neurodegeneration","volume":"620","author":"MF Gulen","year":"2023","journal-title":"Nature"},{"key":"pone.0351312.ref037","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-023-02897-5","article-title":"Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum","volume":"20","author":"R Gamage","year":"2023","journal-title":"J Neuroinflammation"},{"key":"pone.0351312.ref038","article-title":"NLRP1 inflammasome involves in learning and memory impairments and neuronal damages during aging process in mice","volume":"17","author":"D Sun","year":"2021","journal-title":"Behav Brain Funct"},{"issue":"1","key":"pone.0351312.ref039","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jmb.2010.11.031","article-title":"Substrate-induced conformational changes occur in all cleaved forms of caspase-6","volume":"406","author":"S Vaidya","year":"2011","journal-title":"J Mol Biol"},{"issue":"12","key":"pone.0351312.ref040","doi-asserted-by":"crossref","first-page":"5044","DOI":"10.1128\/iai.61.12.5044-5048.1993","article-title":"In vivo induction of apoptosis (programmed cell death) in mouse thymus by administration of lipopolysaccharide","volume":"61","author":"YH Zhang","year":"1993","journal-title":"Infect Immun"},{"issue":"10","key":"pone.0351312.ref041","doi-asserted-by":"crossref","first-page":"5014","DOI":"10.4049\/jimmunol.152.10.5014","article-title":"Sepsis-induced apoptosis of the thymocytes in mice","volume":"152","author":"SD Wang","year":"1994","journal-title":"J Immunol"},{"key":"pone.0351312.ref042","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev.nutr.22.011602.092259","article-title":"How host-microbial interactions shape the nutrient environment of the mammalian intestine","volume":"22","author":"LV Hooper","year":"2002","journal-title":"Annu Rev Nutr"},{"issue":"5717","key":"pone.0351312.ref043","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1126\/science.1104816","article-title":"Host-bacterial mutualism in the human intestine","volume":"307","author":"F B\u00e4ckhed","year":"2005","journal-title":"Science"},{"issue":"23","key":"pone.0351312.ref044","doi-asserted-by":"crossref","first-page":"20431","DOI":"10.1074\/jbc.M110333200","article-title":"TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells","volume":"277","author":"MT Abreu","year":"2002","journal-title":"J Biol Chem"},{"issue":"4","key":"pone.0351312.ref045","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1053\/j.gastro.2004.01.007","article-title":"Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells","volume":"126","author":"J-M Otte","year":"2004","journal-title":"Gastroenterology"},{"key":"pone.0351312.ref046","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1152\/ajpgi.00120.2012","article-title":"Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice","volume":"303","author":"E Im","year":"2012","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"issue":"3","key":"pone.0351312.ref047","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/pr.2014.207","article-title":"Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis","volume":"77","author":"D Meng","year":"2015","journal-title":"Pediatr Res"},{"issue":"10","key":"pone.0351312.ref048","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/jat.2773","article-title":"Corn oil as a vehicle in drug development exerts a dose-dependent effect on gene expression profiles in rat thymus","volume":"32","author":"X-C Geng","year":"2012","journal-title":"J Appl Toxicol"},{"key":"pone.0351312.ref049","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/toxsci\/56.1.156","article-title":"Influence of corn oil and diet on reproduction and the kidney in female Sprague-Dawley rats","volume":"56","author":"M Sato","year":"2000","journal-title":"Toxicol Sci"},{"key":"pone.0351312.ref050","doi-asserted-by":"crossref","first-page":"114548","DOI":"10.1016\/j.physbeh.2024.114548","article-title":"Corn oil and Soybean oil effect as vehicles on behavioral and oxidative stress profiles in developmentally exposed offspring mice","volume":"280","author":"L Berroug","year":"2024","journal-title":"Physiol Behav"},{"key":"pone.0351312.ref051","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1472-6793-10-2","article-title":"Different stress-related phenotypes of BALB\/c mice from in-house or vendor: alterations of the sympathetic and HPA axis responsiveness","volume":"10","author":"J Olfe","year":"2010","journal-title":"BMC Physiol"},{"key":"pone.0351312.ref052","doi-asserted-by":"crossref","first-page":"299","DOI":"10.3389\/fnagi.2019.00299","article-title":"Age and sex influence the neuro-inflammatory response to a peripheral acute LPS challenge","volume":"11","author":"V Murtaj","year":"2019","journal-title":"Front Aging Neurosci"},{"key":"pone.0351312.ref053","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.2353\/ajpath.2007.060974","article-title":"Activation of caspase-6 in aging and mild cognitive impairment","volume":"170","author":"S Albrecht","year":"2007","journal-title":"Am J Pathol"},{"issue":"1","key":"pone.0351312.ref054","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1186\/s12964-023-01287-x","article-title":"Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-I\u03baB\u03b1 axis in liver inflammation","volume":"21","author":"Y Lin","year":"2023","journal-title":"Cell Commun Signal"},{"key":"pone.0351312.ref055","doi-asserted-by":"crossref","first-page":"2411375","DOI":"10.1002\/advs.202411375","article-title":"Caspase-6\/Gasdermin C-mediated tumor cell pyroptosis promotes colorectal cancer progression through CXCL2-dependent recruitment of myeloid-derived suppressor cells","volume":"12","author":"H Gao","year":"2025","journal-title":"Adv Sci"},{"key":"pone.0351312.ref056","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/imm.13633","article-title":"Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer","volume":"169","author":"L Qi","year":"2023","journal-title":"Immunology"},{"issue":"3","key":"pone.0351312.ref057","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41419-021-03506-0","article-title":"Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits","volume":"12","author":"A No\u00ebl","year":"2021","journal-title":"Cell Death Dis"},{"key":"pone.0351312.ref058","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/j.bbi.2020.04.015","article-title":"Preclinical validation of the micropipette-guided drug administration (MDA) method in the maternal immune activation model of neurodevelopmental disorders","volume":"88","author":"J Scarborough","year":"2020","journal-title":"Brain Behav Immun"},{"issue":"6","key":"pone.0351312.ref059","doi-asserted-by":"crossref","first-page":"101379","DOI":"10.1016\/j.jbc.2021.101379","article-title":"Caspase-6 promotes activation of the caspase-11-NLRP3 inflammasome during gram-negative bacterial infections","volume":"297","author":"M Zheng","year":"2021","journal-title":"J Biol Chem"},{"key":"pone.0351312.ref060","article-title":"Identification of bacterial muramyl dipeptide as activator of the NALP3\/Cryopyrin inflammasome bacterial products, leading to the activation of caspase-1 independent of TLRs","volume":"14","author":"F Martinon","year":"1929","journal-title":"Curr Biol"},{"key":"pone.0351312.ref061","article-title":"Monomeric and Polymeric Gram-Negative Peptidoglycan but Not Purified LPS Stimulate the Drosophila IMD Pathway infections activate protease and phenoloxidase cas-cades that lead to localized coagulation and melan-ization (Hoffmann, 1995). 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