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Neuropathological features include aggregated \u03b2-amyloid (A\u03b2) accumulation, neuroinflammation, and oxidative stress in the brain. Daphnetin (DAPH), a natural coumarin derivative, has the potential for inhibiting inflammatory and oxidative responses. We explored neuroprotective roles of DAPH treatment in the APP\/PS1 transgenic mouse AD model. DAPH ameliorated spatial learning disabilities in Morris water maze tests and reduced A\u03b2 deposition, assessed by immunohistochemistry. It also reduced the A\u03b2 content in supernatants of neurons from fetal APP\/PS1 mice, assessed by cell-based soluble ELISA. Molecular docking and fluorescence resonance energy transfer-based assay results suggested that DAPH could directly inhibit BACE1 activity. Furthermore, in vitro experiments utilizing isolated rat neurons assessing RNA expression profiling, immunofluorescence, TUNEL assay, and Western-blot analysis, suggested the potential of DAPH for regulating BDNF and GM-CSF expression and mitigating A\u03b21-42-induced cortical injury, synaptic loss, and apoptosis. HO-1 and Nrf2 mRNA and protein expression were also increased in a dose-dependent manner. These results underscore the potential of DAPH as a neuroprotective agent in reversing memory deficits associated with AD and bolster its candidacy as a multitarget natural small-molecule drug for AD patients.<\/jats:p>","DOI":"10.1093\/jnen\/nlae043","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T20:19:46Z","timestamp":1717186786000},"page":"670-683","source":"Crossref","is-referenced-by-count":8,"title":["Daphnetin protects neurons in an Alzheimer disease mouse model and normal rat neurons by inhibiting BACE1 activity and activating the Nrf2\/HO-1 pathway"],"prefix":"10.1093","volume":"83","author":[{"given":"Xin","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huanyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanchu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University , Shaanxi, P. R. 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