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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Neuroinflammation plays a central role in Alzheimer\u2019s disease (AD). Glycyrrhizin (GL), a major component of licorice, exhibits anti-inflammatory effects, but its effects on AD pathology remain unclear. To investigate the effects of GL (18\u03b2-glycyrrhizin, 18\u03b2-GL) and its stereoisomer (18\u03b1-glycyrrhizin, 18\u03b1-GL) on cognitive function, neuroinflammation, and AD pathology in senescence-accelerated mouse prone 8 (SAMP8; P8) mice, 40-week-old P8 male mice, an AD model due to aging, and the control (senescence-accelerated mouse resistant 1, SAMR1; R1) mice were treated with 18\u03b2-GL, 18\u03b1-GL and physiological saline (control) for 12 weeks (n = 6 in each group). Cognitive function was evaluated using a step-through passive avoidance test. Plasma levels of \u03b1-Klotho, IGF-1, 2\u2032,3\u2032-cyclic GMP-AMP (2\u2032,3\u2032-cGAMP), HMGB1, IL-6, and TNF-\u03b1 were measured by ELISA. Hippocampal microglial activation (Iba1), amyloid-\u03b2 (A\u03b2) deposition, and phosphorylated tau (p-Tau) were assessed by immunohistochemistry. Aged P8 mice showed impaired memory, decreased \u03b1-Klotho and IGF-1 levels, and increased inflammatory markers compared with R1 mice. GL significantly improved memory performance, reduced inflammatory markers, and suppressed Iba1 activation, as well as A\u03b2 and p-Tau accumulation. These effects were associated with inhibition of the cGAS\u2013STING pathway, as indicated by reduced 2\u2032,3\u2032-cGAMP and HMGB1 levels. GL ameliorates AD pathology by inhibiting neuroinflammation, suggesting its therapeutic potential for AD.<\/jats:p>","DOI":"10.3390\/ijms27167399","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"7399","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycyrrhizin Ameliorates Learning and Memory Impairment via Inhibition of Neuroinflammation in an Alzheimer\u2019s Disease Mouse Model SAMP8"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-0974","authenticated-orcid":false,"given":"Guifeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Acupuncture and Moxibustion Medical Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Hiramoto","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7315-8835","authenticated-orcid":false,"given":"Ning","family":"Ma","sequence":"additional","affiliation":[{"name":"Graduate School of Health Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan"},{"name":"Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1495-2817","authenticated-orcid":false,"given":"Shiho","family":"Ohnishi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-9098","authenticated-orcid":false,"given":"Nobuji","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Matsusaka R&D Center, Cokey Co., Ltd., Matsusaka 515-0041, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariko","family":"Murata","sequence":"additional","affiliation":[{"name":"Graduate School of Health Science, Suzuka University of Medical Science, Suzuka 510-0293, Mie, Japan"},{"name":"Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu 514-8507, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7525-7658","authenticated-orcid":false,"given":"Shosuke","family":"Kawanishi","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka 513-8670, Mie, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10787-025-02041-0","article-title":"A mechanistic insight of neuro-inflammation signaling pathways and implication in neurodegenerative disorders","volume":"34","author":"Shafi","year":"2026","journal-title":"Inflammopharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/s43587-023-00441-x","article-title":"Longevity factor klotho enhances cognition in aged nonhuman primates","volume":"3","author":"Castner","year":"2023","journal-title":"Nat. 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