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This study aimed to clarify the regulatory mechanism underlying the <jats:italic>Pg<\/jats:italic>OMV\u2010induced AD\u2010like phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>We intraperitoneally injected <jats:italic>Pg<\/jats:italic>OMVs into the periphery of wild\u2010type and <jats:italic>CatB<\/jats:italic> knockout mice for 4 or 8\u2009weeks to assess the effect of CatB on <jats:italic>Pg<\/jats:italic>OMV\u2010induced AD pathology. Mice were evaluated for cognitive change, tau phosphorylation, microglial activation, neuroinflammation and synapse loss. Microglial and primary neuron culture were prepared to verify the in\u00a0vivo results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CatB deficiency significantly alleviated <jats:italic>Pg<\/jats:italic>OMV\u2010induced cognitive dysfunction, microglia\u2010mediated neuroinflammation, tau hyperphosphorylation and synapse loss. Subsequent transcriptomic analysis, immunofluorescence and immunoblotting suggested that CatB modulates microglia\u2010mediated neuroinflammation through stress\u2010activated protein kinases (SAPK)\/Jun amino\u2010terminal kinases (JNK) signals after administration of <jats:italic>Pg<\/jats:italic>OMVs, which in turn regulates neuronal tau phosphorylation and synapse loss in a SAPK\/JNK\u2010dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study unveils a previously unknown role of CatB in regulating <jats:italic>Pg<\/jats:italic>OMV\u2010induced AD pathology.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jcpe.14109","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T06:35:08Z","timestamp":1735281308000},"page":"434-456","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cathepsin B Modulates Alzheimer's Disease Pathology Through <scp>SAPK<\/scp>\/<scp>JNK<\/scp> Signals Following Administration of\u00a0<i>Porphyromonas gingivalis<\/i>\u2010Derived Outer Membrane Vesicles"],"prefix":"10.1111","volume":"52","author":[{"given":"Muzhou","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoucheng","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology China Medical University  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