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

Yebo Gu, Zhou Wu, Fan Zeng, Muzhou Jiang, Jessica L. Teeling, Junjun Ni, Ichiro Takahashi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)61-74
Number of pages14
JournalJournal of Alzheimer's Disease
Volume78
Issue number1
DOIs
Publication statusPublished - 2020

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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