Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause Alzheimer's disease-like pathology and cognitive decline

Abstract

Abstract Background Periodontitis is a risk factor linked to Alzheimer's disease (AD), and amyloid-beta (Aβ) is a pathological characteristic of AD. Increasing evidence suggests that periodontitis contributes to the formation and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in mice. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (IFITM3), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, it is unknown whether periodontitis also increases type I interferons in the brain and induces AD-like pathology by triggering the innate immune response of glial cells and activating the IFITM3-Aβ axis. Whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains elusive. Methods We evaluated the effects of periodontitis on cognitive impairment in C57BL/6J and APP/PS1 mice using behavioral tests. The effects of Periodontitis/Pg on microglia and astrocytes were measured using qRT-PCR, western blotting, and histological staining. Results Pg-induced periodontitis caused cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, periodontitis increased the level of interferon (IFN)-β, IFITM3, and Aβ deposition of C57BL/6J and APP/PS1 mice in the brain. And we identified Pg DNA, apoptotic cells, glial activation, and the expression of inflammatory mediators in the brain of a mouse periodontitis model. Furthermore, our results confirmed that astrocytes were the main responders to Pg-induced innate immunity and inflammation in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands, and saliva. Conclusions We define a previously unidentified link between periodontitis and cognitive decline, and provide new evidence linking oral pathogenic bacteria-induced innate immunity and neuroinflammation to AD pathogenesis and cognitive decline in part by disrupting the BBB, triggering neuroinflammation and increasing IFITM3 in glial cells for Aβ deposition. Periodontitis also exacerbates innate immunity and cognitive impairment in AD mice, which implies the necessity of preventing and controlling periodontal disease in AD patients.