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 (PgLPS) 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 PgLPS (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 A beta(42) accumulation in neurons (r = 0.8635, p < 0.0001). In cultured MG6 microglia, the PgLPS-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 PgLPS-stimulated microglia (MCM) but not PgLPS increased the productions of A beta PP, CatB, and A beta(42), 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 PgLPS simultaneously induces inflammationdependent 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.