Systemic Exposure to Lipopolysaccharide from Porphyromonas gingivalis Induces Bone Loss-Correlated Alzheimer’s Disease-Like Pathologies in Middle-Aged Mice

Article type: Research Article

Authors: Gu, Yebo^a | Wu, Zhou^{b; c; *} | Zeng, Fan^b | Jiang, Muzhou^b | Teeling, Jessica L.^d | Ni, Junjun^{b; e; *} | Takahashi, Ichiro^{a; *}

Affiliations: [a] Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, Japan | [b] Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan | [c] OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan | [d] Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, United Kingdom | [e] Key Laboratory of Molecular Medicine, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China

Correspondence: [*] Correspondence to: Zhou Wu, Department of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan. Tel.:/Fax: +81 92 642 6414; E-mail: zhouw@dent.kyushu-u.ac.jp.; Junjun Ni, Key Laboratory of Molecular Medicine, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Tel.: +86 17600 397519; E-mail: nijunjun@bit.edu.cn.; Ichiro Takahashi, Section of Orthodontics and Dentofacial Orthopedics, Division of Oral Health, Growth and Development, Faculty of Dental Science, Kyushu University, Fukuoka, 812-8582, Japan. Tel.: +81 92 642 6394; Fax: +81 92 642 6398; E-mail: takahashi@dent.kyushu-u.ac.jp.

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 Aβ42 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 AβPP, CatB, and Aβ42, 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.

Keywords: Alzheimer’s disease, amyloid-β, bone loss, interleukin-6, interleukin-17, lipopolysaccharide from Porphyromonas gingivalis, memory decline, microglia, systemic inflammation

DOI: 10.3233/JAD-200689

Journal: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 61-74, 2020