Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated cognitive decline in APP/PS1 mice.
Elevated levels of interferon (IFN)-β, , and amyloid-beta (Aβ) deposition were observed in the brains of both mouse models following periodontitis.
Pg DNA, glial activation, and inflammatory mediators were identified in the brains of mice with Pg-induced periodontitis.
Astrocytes were confirmed as the primary responders to Pg-induced innate immunity and inflammation in both laboratory and living models.
Periodontitis was associated with increased IFITM3 expression in periodontal tissue and salivary glands.
Simplified
BACKGROUND: Periodontitis is a risk factor linked to Alzheimer's disease (AD), and characterized by amyloid-beta (Aβ) pathology. Mounting evidence suggests a contributory role of periodontitis in the onset and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in murine models. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, whether periodontitis triggers an increase in type I interferons in the brain, subsequently inducing AD-like pathology by eliciting the innate immune response of glial cells and activating the IFITM3-Aβ axis, remains unclear. Additionally, the question of whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains unanswered.
METHODS: We assessed the impact of Pg-induced 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 quantitative reverse transcriptase PCR (qRT-PCR), western blotting, and histological staining.
RESULTS: Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, Pg-induced periodontitis elevated the levels of interferon (IFN)-β, IFITM3, and Aβ deposition in the brains of both C57BL/6J and APP/PS1 mice. We also identified Pg DNA, glial activation, and the expression of inflammatory mediators in the brain of a Pg-induced periodontitis model. Additionally, our findings confirmed astrocytes as the primary responders to Pg-induced innate immunity and inflammation both in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands.
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, partly through increased blood-brain barrier (BBB) permeability, triggered neuroinflammation, and elevated IFITM3 in glial cells for Aβ deposition. Moreover, periodontitis exacerbates innate immunity and cognitive impairment in AD mice, underscoring the importance of preventive and therapeutic strategies for periodontal disease in AD patients.
Key numbers
49.09±3.06 s vs. 40.64±2.92 s
Increase in Escape Latency
C57-P mice took longer to find hidden platforms on day 2.
46.07±4.33 vs. 86.43±2.53
Bone Volume Reduction
Bone volume per total volume in C57-P vs. C57 groups.
Aβ/GFAP and Aβ/IBA1 co-staining
Aβ Accumulation Increase
Significant Aβ accumulation observed in the brains of periodontitis mice.
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Declarations. Ethics approval and consent to participate: All animal procedures used in this study were approved by the Institutional Animal Care and Use Committee of Dalian Medical University (No. AEE22006). All patients were approved by the ethics committee at the Affiliated Stomatological Hospital of Dalian Medical University School of Stomatology, Dalian, China (No. 2022002). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
