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CD31, also named platelet endothelial cell adhesion molecule (PECAM), is a surface membrane protein of both endothelial and immune cells and plays important roles in the interaction between the vascular and immune systems. In this review, we focus on research regarding CD31 biological actions in the pathological process that may contribute to AD based on the following rationales. First, endothelial, leukocyte and soluble forms of CD31 play multi-roles in regulating transendothelial migration, increasing blood\u2013brain barrier (BBB) permeability and resulting in neuroinflammation. Second, CD31 expressed by endothelial and immune cells dynamically modulates numbers of signaling pathways, including Src family kinases, selected G proteins, and \u03b2-catenin which in turn affect cell-matrix and cell\u2013cell attachment, activation, permeability, survival, and ultimately neuronal cell injury. In endothelia and immune cells, these diverse CD31-mediated pathways act as a critical regulator in the immunity-endothelia-brain axis, thereby mediating AD pathogenesis in ApoE4 carriers, which is the major genetic risk factor for AD. This evidence suggests a novel mechanism and potential drug target for CD31 in the background of genetic vulnerabilities and peripheral inflammation for AD development and progression.<\/jats:p>","DOI":"10.1177\/0271678x231170041","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T02:20:26Z","timestamp":1681352426000},"page":"1027-1041","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":38,"title":["CD31 as a probable responding and gate-keeping protein of the blood-brain barrier and the risk of Alzheimer\u2019s disease"],"prefix":"10.1177","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0608-8520","authenticated-orcid":false,"given":"Zhengrong","family":"Zhang","sequence":"first","affiliation":[{"name":"Departments of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 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