{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:54:00Z","timestamp":1777949640500,"version":"3.51.4"},"reference-count":45,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82401823"],"award-info":[{"award-number":["82401823"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82471464"],"award-info":[{"award-number":["82471464"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2026,6]]},"abstract":"Abstract<\/jats:title>\n \n Background and Purpose<\/jats:title>\n \n Cognitive impairment poses a major challenge in neurodegenerative diseases and inflammatory brain disorders due to limited treatment options. The voltage\u2010gated sodium channel Na\n V<\/jats:sub>\n 1.6 is associated with synaptic plasticity and cognitive decline in APP\/PS1 mice. DAPT, a \u03b3\u2010secretase inhibitor that blocks Notch signalling, has variable cognitive effects depending on dosage. This study investigates the dose\u2010dependent effects of DAPT on cognition in C57BL\/6 male mice, elucidating its mechanisms through Na\n V<\/jats:sub>\n 1.6 channels, Notch signalling, synaptic plasticity, and neurogenesis.\n <\/jats:p>\n <\/jats:sec>\n \n Experimental Approach<\/jats:title>\n \n Mice received unilateral stereotactic injections in the right hemisphere of low\u2010dose DAPT (1\u00a0\u03bcg\u00b7\u03bcl\n \u22121<\/jats:sup>\n ), high\u2010dose DAPT (2\u00a0\u03bcg\u00b7\u03bcl\n \u22121<\/jats:sup>\n ), or DMSO (control). Cognitive abilities were evaluated using the Morris Water Maze and Y\u2010maze, western blots, immunofluorescence, and RT\u2010qPCR analysed Na\n V<\/jats:sub>\n 1.6, synaptic proteins, NMDA\/AMPA receptors, and neuroinflammatory markers. Neurogenesis was assessed via Nissl and doublecortin (DCX) staining. Primary neuron experiments examined DAPT effects on Na\n V<\/jats:sub>\n 1.6 interactions.\n <\/jats:p>\n <\/jats:sec>\n \n Key Results<\/jats:title>\n \n Low\u2010dose DAPT significantly improved cognition, suppressed Notch pathway genes, reduced Na\n V<\/jats:sub>\n 1.6, and up\u2010regulated synaptic proteins, NMDA\/AMPA receptors, and neuronal markers in vivo\/in vitro. In primary culture neurons, DAPT reduced Notch\u20101\/NICD with TTX but not ATX\u2010II. Inflammatory markers\/cytokines were unchanged. In vitro, 5\u2010\u03bcM DAPT decreased Na\n V<\/jats:sub>\n 1.6, increased Notch receptors and reduced Notch\u20101\/HES\u20101 mRNA. Low\u2010dose DAPT enhanced neurogenesis (increased dentate gyrus DCX\n +<\/jats:sup>\n cells). Molecular docking confirmed favourable DAPT\u2010 Na\n V<\/jats:sub>\n 1.6 interactions.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion and Implications<\/jats:title>\n \n Low\u2010dose DAPT improved cognitive function in C57BL\/6 male mice, by modulating the Na\n V<\/jats:sub>\n 1.6\/Notch axis and enhancing neurogenesis, indicating its potential as a therapeutic strategy for Alzheimer's\u2010related cognitive decline.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bph.70369","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T09:58:23Z","timestamp":1771322303000},"page":"2913-2931","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A low dose of the \u03b3\u2010secretase inhibitor DAPT improves learning and memory by regulating the Na\n V<\/sub>\n 1.6\/Notch axis in C57BL\/6 male mice"],"prefix":"10.1111","volume":"183","author":[{"given":"Bakhtawar","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao\u2010Qin","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kabir","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Khalid","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin\u2010Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue\u2010Lin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Basic Medical Sciences, Liaoning Provincial Key Laboratory of Cerebral Diseases, National\u2010Local Joint Engineering Research Center for Drug\u2010Research and Development (R&D) of Neurodegenerative Diseases Dalian Medical University Dalian 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