AimPorphyromonas gingivalis, a consensus periodontal pathogen, is thought to be involved in Alzheimer's disease (AD) progression, and P. gingivalis‐derived outer membrane vesicles (PgOMVs) are a key toxic factor in inducing AD pathology. This study aimed to clarify the regulatory mechanism underlying the PgOMV‐induced AD‐like phenotype.Materials and MethodsWe intraperitoneally injected PgOMVs into the periphery of wild‐type and CatB knockout mice for 4 or 8 weeks to assess the effect of CatB on PgOMV‐induced 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 vivo results.ResultsCatB deficiency significantly alleviated PgOMV‐induced cognitive dysfunction, microglia‐mediated neuroinflammation, tau hyperphosphorylation and synapse loss. Subsequent transcriptomic analysis, immunofluorescence and immunoblotting suggested that CatB modulates microglia‐mediated neuroinflammation through stress‐activated protein kinases (SAPK)/Jun amino‐terminal kinases (JNK) signals after administration of PgOMVs, which in turn regulates neuronal tau phosphorylation and synapse loss in a SAPK/JNK‐dependent manner.ConclusionOur study unveils a previously unknown role of CatB in regulating PgOMV‐induced AD pathology.
{"title":"Cathepsin B Modulates Alzheimer's Disease Pathology Through SAPK/JNK Signals Following Administration of Porphyromonas gingivalis‐Derived Outer Membrane Vesicles","authors":"Muzhou Jiang, Ziming Ge, Shoucheng Yin, Yanqing Liu, Hanyu Gao, Lijie Lu, Hongyan Wang, Chen Li, Junjun Ni, Yaping Pan, Li Lin","doi":"10.1111/jcpe.14109","DOIUrl":"https://doi.org/10.1111/jcpe.14109","url":null,"abstract":"Aim<jats:styled-content style=\"fixed-case\"><jats:italic>Porphyromonas gingivalis</jats:italic></jats:styled-content>, a consensus periodontal pathogen, is thought to be involved in Alzheimer's disease (AD) progression, and <jats:styled-content style=\"fixed-case\"><jats:italic>P. gingivalis</jats:italic></jats:styled-content>‐derived outer membrane vesicles (<jats:italic>Pg</jats:italic>OMVs) are a key toxic factor in inducing AD pathology. This study aimed to clarify the regulatory mechanism underlying the <jats:italic>Pg</jats:italic>OMV‐induced AD‐like phenotype.Materials and MethodsWe intraperitoneally injected <jats:italic>Pg</jats:italic>OMVs into the periphery of wild‐type and <jats:italic>CatB</jats:italic> knockout mice for 4 or 8 weeks to assess the effect of CatB on <jats:italic>Pg</jats:italic>OMV‐induced 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 vivo results.ResultsCatB deficiency significantly alleviated <jats:italic>Pg</jats:italic>OMV‐induced cognitive dysfunction, microglia‐mediated neuroinflammation, tau hyperphosphorylation and synapse loss. Subsequent transcriptomic analysis, immunofluorescence and immunoblotting suggested that CatB modulates microglia‐mediated neuroinflammation through stress‐activated protein kinases (SAPK)/Jun amino‐terminal 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‐dependent manner.ConclusionOur study unveils a previously unknown role of CatB in regulating <jats:italic>Pg</jats:italic>OMV‐induced AD pathology.","PeriodicalId":15380,"journal":{"name":"Journal of Clinical Periodontology","volume":"12 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}