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The upregulation of polymerase \u03b4\u2010interacting protein 2 (Poldip2) was involved in aggravating BBB disruption following ischemic stroke. This study aimed to investigate whether Poldip2\u2010mediated BBB disruption and cerebral edema formation in mouse bacterial meningitis (BM) model occur via induction of AQP4 polarity loss.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Mouse BM model was induced by injecting mice with group B hemolytic streptococci via posterior cistern. Recombinant human Poldip2 (rh\u2010Poldip2) was administered intranasally at 1\u00a0hour after BM induction. Small interfering ribonucleic acid (siRNA) targeting Poldip2 was administered by intracerebroventricular (i.c.v) injection at 48\u00a0hours before BM induction. A specific inhibitor of matrix metalloproteinases (MMPs), UK383367, was administered intravenously at 0.5\u00a0hour before BM induction. Western blotting, immunofluorescence staining, quantitative real\u2010time PCR, neurobehavioral test, brain water content test, Evans blue (EB) permeability assay, transmission electron microscopy (TEM), and gelatin zymography were carried out. The results showed that Poldip2 was upregulated and AQP4 polarity was lost in mouse BM model. Both Poldip2 siRNA and UK383367 improved neurobehavioral outcomes, alleviated brain edema, preserved the integrity of BBB, and relieved the loss of AQP4 polarity in BM model. Rh\u2010Poldip2 upregulated the expression of MMPs and glial fibrillary acidic protein (GFAP) and downregulated the expression of \u03b2\u2010dystroglycan (\u03b2\u2010DG), zonula occludens\u20101 (ZO\u20101), occludin, and claudin\u20105; whereas Poldip2 siRNA downregulated the expression of MMPs and GFAP, and upregulated \u03b2\u2010DG, ZO\u20101, occludin, and claudin\u20105. Similarly, UK383367 downregulated the expression of GFAP and upregulated the expression of \u03b2\u2010DG, ZO\u20101, occludin, and claudin\u20105.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Poldip2 inhibition alleviated brain edema and preserved the integrity of BBB partially by relieving the loss of AQP4 polarity via MMPs\/\u03b2\u2010DG pathway.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.13446","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T07:52:22Z","timestamp":1597305142000},"page":"1288-1302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Poldip2 mediates blood\u2010brain barrier disruption and cerebral edema by inducing AQP4 polarity loss in mouse bacterial meningitis model"],"prefix":"10.1111","volume":"26","author":[{"given":"Meng","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Anatomy Chongqing Medical 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