AUTHOR=Gong Ting , Chen Qi , Mao Hongchen , Zhang Yao , Ren Huan , Xu Mengmeng , Chen Hong , Yang Deqin 

TITLE=Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 12 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.925435

DOI=10.3389/fcimb.2022.925435

ISSN=2235-2988

ABSTRACT=Background: Porphyromonas gingivalis (Pg), the keystone pathogen in chronic periodontitis, was reported to initiate Alzheimer’s disease pathologies in preclinical studies. However, the specific mechanisms and signaling pathways acting on the brain still need to be further explored. Outer membrane vesicles are derived from Gran-negative bacteria and contain many virulence factors of bacteria. We hypothesized that outer membrane vesicles are important weapon of Porphyromonas gingivalis to initiate Alzheimer’s disease pathologies. 
Methods: Outer membrane vesicles of Porphyromonas gingivalis (Pg OMVs, 4 mg/kg) or saline were delivered to fourteen-month-old mice by oral gavage every other day for 8 weeks. Behavioral alterations were assessed by open filed test, Morris water maze and Y-maze test. Blood brain barrier permeability, neuroinflammation, tau phosphorylation and NLRP3 inflammasome related protein were analyzed. 
Results: Pg OMVs impaired memory and learning ability of mice, decreased tight junctions related gene expression ZO-1, occludin, claudin-5 and occludin protein expression in hippocampus. Pg OMVs could be detected in hippocampus and cortex three days after oral gavage. Furthermore, Pg OMVs activated both astrocytes and microglia, elevated IL-1β, tau phosphorylation on Thr231 site and NLRP3 inflammasome related protein expression in the hippocampus. In in vitro studies, Pg OMVs (5 µg/ml) stimulation increased the mRNA and immunofluorescence of NLRP3 in BV2 microglia, which were significantly inhibited by NLRP3 inhibitor MCC950. In contrast, the tau phosphorylation in N2a neurons were enhanced after treatment with conditioned medium from Pg OMVs-stimulated microglia, which was attenuated after pre-treatment with MCC950.
Conclusions: These results indicate that Pg OMVs prompted memory dysfunction, neuroinflammation, tau phosphorylation and triggered NLRP3 inflammasome in the brain of middle-aged mice. We propose that Pg OMVs play an important role in activating neuroinflammation in the AD-like pathology triggered by Porphyromonas gingivalis, and NLRP3 inflammasome activation is a possible mechanism.