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In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Male APP\/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a\u2010sw cells also were employed to further uncover the mechanism of astrocytic Lf on \u03b2\u2010amyloid (A\u03b2) production.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, A\u03b2 burden and tau hyperphosphorylation in APP\/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP\/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p\u2010APP (Thr668) expression in N2a\u2010sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p\u2010APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf\u2010induced p\u2010APP down\u2010regulation in N2a\u2010sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low\u2010density lipoprotein receptor\u2010related protein 1 (LRP1) knockdown significantly reversed the hLf\u2010induced p38 activation and p\u2010APP down\u2010regulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited A\u03b2 production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v181.6\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v181.6\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16161","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T05:52:45Z","timestamp":1686635565000},"page":"896-913","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Astrocyte\u2010derived lactoferrin reduces \u03b2\u2010amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP\/PS1 transgenic mice"],"prefix":"10.1111","volume":"181","author":[{"given":"Yong\u2010Gang","family":"Fan","sequence":"first","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuang","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling\u2010Xiao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ri\u2010Le","family":"Ge","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong\u2010Qiu","family":"Pang","sequence":"additional","affiliation":[{"name":"College of Life and Health Sciences Northeastern University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da\u2010Long","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hang","family":"Ren","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting\u2010Yao","family":"Wu","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Jinzhou Medical University  Jinzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan\u2010Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhan\u2010You","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province Health Sciences Institute of China Medical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,7,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-191181"},{"issue":"1","key":"e_1_2_13_3_1","first-page":"S1","article-title":"THE CONCISE GUIDE TO PHARMACOLOGY 2021\/22: Introduction and other protein targets","volume":"178","author":"Alexander S. 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