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Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated Alzheimer’s disease-like pathologies in middle-aged mice

Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated Alzheimer’s disease-like pathologies in middle-aged mice
Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated Alzheimer’s disease-like pathologies in middle-aged mice

Background: Alzheimer's disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (P gLPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to P gLPS (r=0.7378, p=0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r=-0.6619, p=0.0052; r=-0.7129, p=0.0019), while that in the cortex was negatively correlated with the memory test latency (r=-0.7198, p=0.0017; p=0.0351, r=-0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aß42 accumulation in neurons (r=0.8635, p<0.0001). In cultured MG6 microglia, the P gLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P gLPS-stimulated microglia (MCM) but not P gLPS increased the productions of AßPP, CatB, and Aß42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to P gLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression.

Alzheimer's disease, amyloid-ß, bone loss, interleukin-17, interleukin-6, lipopolysaccharide from Porphyromonas gingivalis, memory decline, microglia, systemic inflammation
1387-2877
61-74
Gu, Yebo
36ac53d7-8268-4527-a301-08ab6e39fd0f
Wu, Zhou
a6e16847-d89a-4b7f-a3a9-4582394de99f
Zeng, Fan
b23758e4-029d-4428-97bf-2613514aac71
Jiang, Muzhou
b59d5fea-c7d6-4b0d-853f-7f51b166bf0f
Teeling, Jessica L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Ni, Junjun
8fd5109a-3c5a-4466-af62-67a66740307f
Takahashi, Ichiro
9afaa189-6089-45d5-921b-075a9ac30748
Gu, Yebo
36ac53d7-8268-4527-a301-08ab6e39fd0f
Wu, Zhou
a6e16847-d89a-4b7f-a3a9-4582394de99f
Zeng, Fan
b23758e4-029d-4428-97bf-2613514aac71
Jiang, Muzhou
b59d5fea-c7d6-4b0d-853f-7f51b166bf0f
Teeling, Jessica L.
fcde1c8e-e5f8-4747-9f3a-6bdb5cd87d0a
Ni, Junjun
8fd5109a-3c5a-4466-af62-67a66740307f
Takahashi, Ichiro
9afaa189-6089-45d5-921b-075a9ac30748

Gu, Yebo, Wu, Zhou, Zeng, Fan, Jiang, Muzhou, Teeling, Jessica L., Ni, Junjun and Takahashi, Ichiro (2020) Systemic exposure to lipopolysaccharide from Porphyromonas gingivalis induces bone loss-correlated Alzheimer’s disease-like pathologies in middle-aged mice. Journal of Alzheimer's Disease, 78 (1), 61-74. (doi:10.3233/JAD-200689).

Record type: Article

Abstract

Background: Alzheimer's disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (P gLPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to P gLPS (r=0.7378, p=0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r=-0.6619, p=0.0052; r=-0.7129, p=0.0019), while that in the cortex was negatively correlated with the memory test latency (r=-0.7198, p=0.0017; p=0.0351, r=-0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aß42 accumulation in neurons (r=0.8635, p<0.0001). In cultured MG6 microglia, the P gLPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P gLPS-stimulated microglia (MCM) but not P gLPS increased the productions of AßPP, CatB, and Aß42, which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to P gLPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression.

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More information

Accepted/In Press date: 30 July 2020
Published date: 27 October 2020
Keywords: Alzheimer's disease, amyloid-ß, bone loss, interleukin-17, interleukin-6, lipopolysaccharide from Porphyromonas gingivalis, memory decline, microglia, systemic inflammation

Identifiers

Local EPrints ID: 447954
URI: http://eprints.soton.ac.uk/id/eprint/447954
ISSN: 1387-2877
PURE UUID: 5b55e3ad-cd64-4061-8ebd-1c3e0c341b0a
ORCID for Jessica L. Teeling: ORCID iD orcid.org/0000-0003-4004-7391

Catalogue record

Date deposited: 26 Mar 2021 17:33
Last modified: 15 Sep 2021 01:49

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Contributors

Author: Yebo Gu
Author: Zhou Wu
Author: Fan Zeng
Author: Muzhou Jiang
Author: Junjun Ni
Author: Ichiro Takahashi

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