{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:10:53Z","timestamp":1789463453421,"version":"build-2803163510"},"reference-count":59,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374175"],"award-info":[{"award-number":["82374175"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) is characterized by amyloid-\u03b2 (A\u03b2) accumulation with impaired lymphatic clearance, yet therapies targeting lymphatic dysfunction remain underexplored. The Neurolymphatic Formula (NLF), a traditional Chinese medicine, demonstrates lymphatic modulation potential, but its mechanistic role in AD remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to elucidate NLF's therapeutic efficacy in AD and investigate whether it enhances central and peripheral lymphangiogenesis via VEGF receptor 3 (VEGFR3) activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated NLF's pharmacological effects on behavior and AD pathology in APP\/PS1 mice, including sunitinib-induced lymphatic impairment models. Underlying mechanisms were explored using network pharmacology, molecular docking, and in vitro assays on human lymphatic endothelial cells (HLECs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In APP\/PS1 mice, 4-week NLF treatment reduced A\u03b2 plaque burden by 43% (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01) and improved spatial memory latency by 35% (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.05). NLF restored meningeal and mesenteric lymphatic density in sunitinib-treated mice to 82% and 133% of baseline, respectively (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01), while upregulating serum VEGFR3 2.3-fold (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01). To validate NLF's molecular basis, coptisine was identified as a representative VEGFR3 ligand (\u22127.1 Kcal\/mol). In vitro, coptisine (25\u2005\u03bcM) enhanced HLEC viability by 60%, accelerated wound closure 2.5-fold, and increased tube junctions by 75% (all\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.01) alongside VEGFR3 upregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NLF alleviates AD pathology by promoting A\u03b2 clearance through VEGFR3-mediated dual modulation of central and peripheral lymphatic systems. The in vitro efficacy of its constituent, coptisine, mechanistically validates this pro-lymphangiogenic pathway, highlighting NLF's therapeutic potential as a holistic lymphatic-targeted AD treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261470114","type":"journal-article","created":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T12:20:01Z","timestamp":1785586801000},"page":"661-678","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurolymphatic formula restores meningeal and peripheral lymphatic function via VEGFR3 activation: Mechanistic validation of coptisine as a key anti-Alzheimer's compound"],"prefix":"10.1177","volume":"113","author":[{"given":"Jiani","family":"Zhang","sequence":"first","affiliation":[{"name":"Beijing University of Chinese 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