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Cited by 298Neuroinflammation and Neurodegeneration MechanismsOral microbiology and periodontitis researchNeurological Disease Mechanisms and Treatments

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

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Zhang, Jing, Yu, Chunbo, Zhang, Xuan, Chen, Huiwen, Dong, Jiachen, Lu, Weili, Song, Zhongchen, Zhou, Wei·2018·Journal of Neuroinflammation
DOI 10.1186/s12974-017-1052-xPMC PMC5810193
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Abstract

BACKGROUND: Porphyromonas 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. METHODS: ). 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. RESULTS: The 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. CONCLUSIONS: Administration 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.

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Fig. 1 Experimental design. P.gingivalis-LPS (5 mg kg−1, i.p.) was administered in the P.gingivalis-LPS group and P.gingivalis-LPS plus TAK group. Seven days after P.gingivalis-LPS administration, cognitive function was assessed by the open field test (OFT), Morris water maze (MWM) test, and passive avoidance test (PAT). The underlying mechanism was further detected by RT-PCR, ELISA, western blot, and immunohistochemistry
Fig. 1 Experimental design. P.gingivalis-LPS (5 mg kg−1, i.p.) was administered in the P.gingivalis-LPS group and P.gingivalis-LPS plus TAK group. Seven days after P.gingivalis-LPS administration, cognitive function was assessed by the open field test (OFT), Morris water maze (MWM) test, and passive avoidance test (PAT). The underlying mechanism was further detected by RT-PCR, ELISA, western blot, and immunohistochemistryCC BY · PubMed Central
Fig. 2 Effects of P.gingivalis-LPS on animal activity. The open field test (OFT) was used to evaluate the spontaneous activities of mice after 7 days of administration, including total distance covered (a), percentage of time spent on central grid (b), percentage of distance covered on central grid (c), number of rearings (d), number of defecations (e), and frequency of grooming (f). Overall, no significant differences were observed between treatment groups
Fig. 2 Effects of P.gingivalis-LPS on animal activity. The open field test (OFT) was used to evaluate the spontaneous activities of mice after 7 days of administration, including total distance covered (a), percentage of time spent on central grid (b), percentage of distance covered on central grid (c), number of rearings (d), number of defecations (e), and frequency of grooming (f). Overall, no significant differences were observed between treatment groupsCC BY · PubMed Central
Fig. 3 Effects of P.gingivalis-LPS on spatial learning of mice during the Morris water maze (MWM) test. Effects of treatment with P.gingivalis-LPS (5 mg kg−1, i.p.) alone or in combination with TAK-242 (5 mg kg−1, i.p.) on latency to find the platform during the acquisition phase of the MWM test. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01 and ***p < 0.001, compared to the control group; #p < 0.05 and ##p < 0.01, compared to the P.gingivalis-LPS group
Fig. 3 Effects of P.gingivalis-LPS on spatial learning of mice during the Morris water maze (MWM) test. Effects of treatment with P.gingivalis-LPS (5 mg kg−1, i.p.) alone or in combination with TAK-242 (5 mg kg−1, i.p.) on latency to find the platform during the acquisition phase of the MWM test. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01 and ***p < 0.001, compared to the control group; #p < 0.05 and ##p < 0.01, compared to the P.gingivalis-LPS groupCC BY · PubMed Central
Fig. 4 Effects of P.gingivalis-LPS on spatial memory and trajectories in the Morris water maze (MWM) test. The platform was removed on the sixth day, and the distance traveled in the target quadrant was compared between the groups. The following parameters were assessed: percentage of the distance covered in the target quadrant (a), percentage of time spent in the target quadrant (b), and number of platform crossings in the target quadrant (c). The percentage of distance, percentage of time, and number of platform crossings in the target quadrant were significantly reduced by P.gingivalis-LPS. The typical trajectories of the P.gingivalis-LPS group approximated the arc of a circle, without any crossings over the original platform (d). Data are presented as mean ± SEM; **p < 0.01, ***p < 0.001, compared to the control group; ##p < 0.01, compared to the P.gingivalis-LPS group
Fig. 4 Effects of P.gingivalis-LPS on spatial memory and trajectories in the Morris water maze (MWM) test. The platform was removed on the sixth day, and the distance traveled in the target quadrant was compared between the groups. The following parameters were assessed: percentage of the distance covered in the target quadrant (a), percentage of time spent in the target quadrant (b), and number of platform crossings in the target quadrant (c). The percentage of distance, percentage of time, and number of platform crossings in the target quadrant were significantly reduced by P.gingivalis-LPS. The typical trajectories of the P.gingivalis-LPS group approximated the arc of a circle, without any crossings over the original platform (d). Data are presented as mean ± SEM; **p < 0.01, ***p < 0.001, compared to the control group; ##p < 0.01, compared to the P.gingivalis-LPS groupCC BY · PubMed Central
Fig. 5 Effects of P.gingivalis-LPS on response and memory of mice in the passive avoidance test (PAT). The PAT was used to evaluate passive avoidance learning in mice following the Morris water maze (MWM) test. The following parameters were determined: latency to enter the dark compartment (a) and error times to enter the dark compartment (b). Administration of P.gingivalis-LPS reduced the latency and increased error times to enter the dark compartment. Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ##p < 0.01 and ###p < 0.001, compared to the P.gingivalis-LPS group
Fig. 5 Effects of P.gingivalis-LPS on response and memory of mice in the passive avoidance test (PAT). The PAT was used to evaluate passive avoidance learning in mice following the Morris water maze (MWM) test. The following parameters were determined: latency to enter the dark compartment (a) and error times to enter the dark compartment (b). Administration of P.gingivalis-LPS reduced the latency and increased error times to enter the dark compartment. Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ##p < 0.01 and ###p < 0.001, compared to the P.gingivalis-LPS groupCC BY · PubMed Central
Fig. 6 Effects of P.gingivalis-LPS on microglia in the hippocampus. Histopathological analysis of brain sections was performed using immunohistochemistry. Microglia were visualized with ionized calcium-binding adaptor molecule 1 (Iba1) (arrows). Activated microglia with irregular protrusions were observed in the P.gingivalis-LPS group (bar = 50 μm)
Fig. 6 Effects of P.gingivalis-LPS on microglia in the hippocampus. Histopathological analysis of brain sections was performed using immunohistochemistry. Microglia were visualized with ionized calcium-binding adaptor molecule 1 (Iba1) (arrows). Activated microglia with irregular protrusions were observed in the P.gingivalis-LPS group (bar = 50 μm)CC BY · PubMed Central
Fig. 7 Effects of P.gingivalis-LPS on microglia in the cortex. Histopathological analysis of brain sections was performed using immunohistochemistry. Microglia were visualized with ionized calcium-binding adaptor molecule 1 (Iba1) (arrows). Activated microglia with irregular protrusions were observed in the P.gingivalis-LPS group (bar = 50 μm)
Fig. 7 Effects of P.gingivalis-LPS on microglia in the cortex. Histopathological analysis of brain sections was performed using immunohistochemistry. Microglia were visualized with ionized calcium-binding adaptor molecule 1 (Iba1) (arrows). Activated microglia with irregular protrusions were observed in the P.gingivalis-LPS group (bar = 50 μm)CC BY · PubMed Central
Fig. 8 Effects of P.gingivalis-LPS on astrocytes in the hippocampus and cortex. Histopathological analysis of brain sections was performed using immunohistochemistry. Astrocytes were visualized with the glial fibrillary acidic protein (GFAP) (a, arrows). Quantification of GFAP levels in the hippocampus and cortex are shown (b, c). Activated astrocytes were significantly increased following P.gingivalis-LPS administration. Activation was attenuated by TAK-242 (bar = 50 μm). Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ###p < 0.001, compared to the P.gingivalis-LPS group
Fig. 8 Effects of P.gingivalis-LPS on astrocytes in the hippocampus and cortex. Histopathological analysis of brain sections was performed using immunohistochemistry. Astrocytes were visualized with the glial fibrillary acidic protein (GFAP) (a, arrows). Quantification of GFAP levels in the hippocampus and cortex are shown (b, c). Activated astrocytes were significantly increased following P.gingivalis-LPS administration. Activation was attenuated by TAK-242 (bar = 50 μm). Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ###p < 0.001, compared to the P.gingivalis-LPS groupCC BY · PubMed Central
Fig. 9 Effects of P.gingivalis-LPS on mRNA and protein expression of inflammatory cytokines. RT-PCR and ELISA were performed to detect mRNA (a, c, e, g), and protein (b, d, f, h) levels of inflammatory cytokines. Administration of P.gingivalis-LPS induced high expression of inflammatory factors on genes and proteins, in comparison to the control group, whereas these changes were reversed by TAK-242. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01, and ***p < 0.001, compared to the control group; #p < 0.05, ##p < 0.01, and ###p < 0.001, compared to the P.gingivalis-LPS group
Fig. 9 Effects of P.gingivalis-LPS on mRNA and protein expression of inflammatory cytokines. RT-PCR and ELISA were performed to detect mRNA (a, c, e, g), and protein (b, d, f, h) levels of inflammatory cytokines. Administration of P.gingivalis-LPS induced high expression of inflammatory factors on genes and proteins, in comparison to the control group, whereas these changes were reversed by TAK-242. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01, and ***p < 0.001, compared to the control group; #p < 0.05, ##p < 0.01, and ###p < 0.001, compared to the P.gingivalis-LPS groupCC BY · PubMed Central
Fig. 10 Effects of P.gingivalis-LPS on mRNA expression of TLR2, TLR3, TLR4, and CD14. The RT-PCR was performed to detect mRNA levels of TLR2, TLR3, TLR4, and CD14 (a–d). The mRNA expression of TLR4 and CD14 was upregulated by P.gingivalis-LPS; however, similar effects were not observed in TLR2 and TLR3. Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ##p < 0.01, compared with the P.gingivalis-LPS group; +++p < 0.001, P.gingivalis-LPS group compared with the E.coli-LPS group
Fig. 10 Effects of P.gingivalis-LPS on mRNA expression of TLR2, TLR3, TLR4, and CD14. The RT-PCR was performed to detect mRNA levels of TLR2, TLR3, TLR4, and CD14 (a–d). The mRNA expression of TLR4 and CD14 was upregulated by P.gingivalis-LPS; however, similar effects were not observed in TLR2 and TLR3. Data are presented as mean ± SEM; ***p < 0.001, compared to the control group; ##p < 0.01, compared with the P.gingivalis-LPS group; +++p < 0.001, P.gingivalis-LPS group compared with the E.coli-LPS groupCC BY · PubMed Central
Fig. 11 P.gingivalis-LPS-induced neuroinflammatory processes via the TLR4/NF-κB signaling pathway. Expression of CD14, TLR4, IRAK1, p65, and p-p65 was measured by western blot analysis (a). Graphs show the semiquantitative analysis of protein levels (b–e). Expression of CD14, TLR4, IRAK1, and p-p65/p65 proteins was upregulated by P.gingivalis-LPS. High expression of these proteins (TLR4, IRAK1, and p-p65/p65) was effectively inhibited by TAK-242. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001, compared to the control group; #p < 0.05, ##p < 0.01, ###p < 0.001, compared to the P.gingivalis-LPS group
Fig. 11 P.gingivalis-LPS-induced neuroinflammatory processes via the TLR4/NF-κB signaling pathway. Expression of CD14, TLR4, IRAK1, p65, and p-p65 was measured by western blot analysis (a). Graphs show the semiquantitative analysis of protein levels (b–e). Expression of CD14, TLR4, IRAK1, and p-p65/p65 proteins was upregulated by P.gingivalis-LPS. High expression of these proteins (TLR4, IRAK1, and p-p65/p65) was effectively inhibited by TAK-242. Data are presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001, compared to the control group; #p < 0.05, ##p < 0.01, ###p < 0.001, compared to the P.gingivalis-LPS groupCC BY · PubMed Central

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Metadata

Authors
Zhang, J., Yu, C., Zhang, X., Chen, H., Dong, J., Lu, W., Song, Z., & Zhou, W.
Affiliations
Shanghai Jiao Tong University (CN)
Corresponding author
  • Song, Zhongchen
  • Zhou, Wei
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2018-02-09
Volume
15
Issue
1
Pages
37-37
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-017-1052-x
PMC
PMC5810193
OpenAlex
W2802436906
Cited by
297
References
43
Citations by year
2026: 22 · 2025: 41 · 2024: 53 · 2023: 49 · 2022: 44 · 2021: 45 · 2020: 25 · 2019: 13 · 2018: 5
FWCI
9.90
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81670992, 81273519)
  • Shanghai Summit & Plateau Disciplines (20152523)
  • Chinese Stomatological Association (CSAY2015-01)
  • Interdisciplinary Program of Shanghai JiaoTong University (YG2015MS07, YG2015MS04)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Porphyromonas gingivalis, lipopolysaccharide, cognitive impairment, neuroinflammation, TLR4 signaling, NF-κB signaling, chronic periodontitis, spatial learning and memory, passive avoidance learning, astrocyte activation, microglial activation, inflammatory cytokines, TAK-242, periodontal pathogens, endotoxin
MeSH terms
Animals, Inflammation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Random Allocation, Sulfonamides, Signal Transduction, Porphyromonas gingivalis, Maze Learning, Toll-Like Receptor 4, Mice, Cognitive Dysfunction

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