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Here, we discovered that both mRNA and protein levels of CD31 (platelet endothelial cell adhesion molecule\u20101, PECAM1), a transmembrane glycoprotein in immunoglobulin superfamily, were significantly higher in the brains of AD individuals and different AD transgenic mice, and the elevated CD31 was related to the recognized AD pathologies. Additional studies demonstrated that systemically knockdown of CD31 in 5xFAD mice significantly improved the cognitive functions with decreased AD hallmark pathologies, including\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010amyloid precipitation and tau hyperphosphorylation. Moreover, CD31 knockdown alleviated neuroinflammation, evidenced by the diminished microglial stimulation and suppressed expression of pro\u2010inflammatory cytokines. Transcriptomic analysis indicated considerable changes in the AD\u2010involved gene expression in 5xFAD mice, and CD31 knockdown rectified imbalanced gene expression. Mechanistically, we further revealed that CD31 knockdown suppressed the expression of STAT1 and IRF1 by reducing histone lactylation at H3K14 and H4K12, thereby modulating the transcriptional programs driving neuroinflammation and AD pathology. These findings illustrate that CD31 may act as a promising target for creating novel therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70665","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:12:44Z","timestamp":1772968364000},"source":"Crossref","is-referenced-by-count":0,"title":["Downregulating Platelet Endothelial Cell Adhesion Molecule\u20101 Enhances Learning and Memory and Alleviates Hallmark Pathologies in Alzheimer's Disease"],"prefix":"10.1002","volume":"7","author":[{"given":"Qiuzhi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China\/Hubei Province For Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Department of Rehabilitation Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan 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For Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China\/Hubei Province For Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shihong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology School of Basic Medicine Key Laboratory of Education Ministry of China\/Hubei Province For Neurological Disorders, Tongji Medical College Huazhong University of Science and Technology  Wuhan China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of 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