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With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti\u2010AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose and Study Design<\/jats:title><jats:p>In this study, the combination of RA and TAC was explored, and a high dose of <jats:sc>d<\/jats:sc>\u2010galactose was used to build an <jats:sc>AD<\/jats:sc> mouse model, which was given at the same time for 4\u2009weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of <jats:sc>AD<\/jats:sc> in mice through RA. In particular, we pay attention to the key role of A\u03b2 and microglia in the pathogenesis of <jats:sc>AD<\/jats:sc>, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by A\u03b2 plaque in the brain of <jats:sc>AD<\/jats:sc> mice and enhancing the ability of microglia to clear A\u03b2 plaque.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results show that the combination of RA and TAC has the best intervention effect on <jats:sc>AD<\/jats:sc> compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA\u2009+\u2009TAC significantly improved body weight, organ index, and behavioral state of <jats:sc>AD<\/jats:sc> mice. Further analysis showed that RA\u2009+\u2009TAC enhanced the antioxidant level of hippocampus and serum of <jats:sc>AD<\/jats:sc> mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic A\u03b21\u201041 and A\u03b21\u201042 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium\u2013binding adapter molecule 1 [Iba\u20101]), increased the expression of M2 microglia marker Arg\u20101, and promoted the release of anti\u2010inflammatory compounds. In addition, RA\u2009+\u2009TAC also inhibited the mRNA expression of TLR4 and NF\u2010\u03baB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase\u20103 by regulating the expression of bcl\u20102\/bax, alleviated TAC\u2010induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and \u03b3\u2010GT reflecting liver function closer to the normal range.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pca.70009","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T08:05:21Z","timestamp":1753949121000},"page":"2022-2038","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Attenuation of Tacrine Combined With Rosmarinic Acid"],"prefix":"10.1002","volume":"36","author":[{"given":"Manyv","family":"Zheng","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory for Modern Drug Delivery &amp; High\u2010Efficiency, School of Pharmaceutical Science and Technology Tianjin University  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingjuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory for Modern Drug Delivery &amp; High\u2010Efficiency, School of Pharmaceutical Science and Technology Tianjin University  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqing","family":"Li","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Chinese Medicine Modernization Tasly Pharmaceutical Group Co, Ltd  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luyao","family":"Tian","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory for Modern Drug Delivery &amp; High\u2010Efficiency, School of Pharmaceutical Science and Technology Tianjin University  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuiping","family":"Zhou","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Chinese Medicine Modernization Tasly Pharmaceutical Group Co, Ltd  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genbei","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Chinese Medicine Modernization Tasly Pharmaceutical Group Co, Ltd  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0050-501X","authenticated-orcid":false,"given":"Wenyuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory for Modern Drug Delivery &amp; High\u2010Efficiency, School of Pharmaceutical Science and Technology Tianjin University  Tianjin China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac177"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2024.115219"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12010-021-03779-3"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1192\/j.eurpsy.2024.432"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12638"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2589-7500(21)00275-2"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/jphp.13165"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21699"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270006288735"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010556"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0258420"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2022.106168"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X18666200807130637"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114305"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12577"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113663"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2016.10.060"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221910637"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23095072"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2022.2045591"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)90526-X"},{"key":"e_1_2_9_23_1","article-title":"Tacrine in Alzheimer's Disease","volume":"328","author":"Eagger S. 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