Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice

Abstract

BackgroundPorphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS) is one of the major pathogenic factors of chronic periodontitis (CP). Few reports on the correlation between P. gingivalis-LPS and cognitive function exist. Thus, the present study aimed to investigate the effects of P. gingivalis-LPS on cognitive function and the associated underlying mechanism in C57BL/6 mice.MethodsThe C57BL/6 mice were injected with P. gingivalis-LPS (5 mg kg−1) either with or without Toll-like receptor 4 (TLR4) inhibitor (TAK-242, 5 mg kg−1). After 7 days, behavioral alterations were assessed with the open field test (OFT), Morris water maze (MWM) test, and passive avoidance test (PAT). The activation of astrocytes and microglia in the cerebral cortex and hippocampus of mice was observed by immunohistochemistry. The expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), TLRs (TLR2, TLR3, and TLR4), and CD14 and the activation of the NF-κB signaling pathway (IRAK1, p65, and p-p65) in the cerebral cortex of the mice were evaluated by RT-PCR, ELISA, and western blot.ResultsThe OFT showed that P. gingivalis-LPS did not affect the initiative and activity of mice. Administration of P. gingivalis-LPS significantly impaired spatial learning and memory during the MWM test and attenuated the ability of passive avoidance learning during the PAT. Both astrocytes and microglia were activated in the cortex and hippocampus. The messenger RNA (mRNA) and protein expression of inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8) was upregulated by P. gingivalis-LPS in the cortex. In addition, the TLR4/NF-κB signaling pathway was activated (TLR4, CD14, IRAK1, and p-p65). These effects were effectively alleviated by TAK-242.ConclusionsAdministration of P. gingivalis-LPS can lead to learning and memory impairment in C57BL/6 mice. This impairment is mediated by activation of the TLR4 signaling pathway. Our study suggests that P. gingivalis-LPS-induced neuroinflammation plays an important role in cognitive impairment. It also reveals that endotoxins of periodontal pathogens could represent a risk factor for cognitive disorders.

Association between periodontitis and cognitive impairment: Analysis of national health and nutrition examination survey (NHANES) III

“…Although the role of systemic inflammation of periodontitis for cognitive impairment is not completely clear, the elevated serum C‐reactive protein and white blood cell count in subjects with periodontitis of this study, compared with healthy groups, might imply the presence of the systemic level of inflammation factors (Table ). Zhang et al () used mice injected with Porphyromonas gingivalis lipopolysaccharide ( P. gingivalis ‐LPS) to investigate the effects of P. gingivalis ‐LPS on cognitive function and the associated underlying mechanism. Both astrocytes and microglia were activated in the cerebral cortex and hippocampus of mice.…”

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…A Multi Conditioning System 2.0 (TSE Systems) was used to perform the passive avoidance test from 11:00 am to 3:00 pm. As described previously, 36 the experimental equipment included a box with a grid floor and two compartments, one that was illuminated and another that was dark. There was a shuttle door to allow the mouse to move freely between the two compartments.…”

Serotype b of Aggregatibacter actinomycetemcomitans triggers pro-inflammatory responses and amyloid beta secretion in hippocampal cells: a novel link between periodontitis and Alzheimer´s disease?

“…These findings evidence a discriminatory capacity of the brain immune response for this periodontopathogen. Of note, experimental infections with P. gingivalis to evaluate neuroinflammation and cognitive impairment have not considered the variability of the different antigens from each bacterial serotype of P. gingivalis [35,36]. Nevertheless, our results show that the serotype b of Aa directly impacts on the pattern of cytokine secretion and, consequently, on neuronal morphology.…”

“…Thus, the chronic presence of LPS of periodontopathogenic bacteria associated to PDis could represent a risk factor for the function of brain cells. Indeed, recent studies have evaluated the effect of the highly prevalent periodontopathogenic bacteria P. gingivalis on neuroinflammation, showing that this bacterial infection induces the secretion of inflammatory cytokines and causes cognitive defects [35,36]. Also, oral infection with P. gingivalis aggravates AD features in an AD transgenic rat model [6] and promotes brain inflammation, neurodegeneration and amyloid beta production in wild type mice [37].…”