Kong Lingwenyao, Li Juanjuan, Gao Lu, Zhao Yonggang, Chen Weixian, Wang Xumeng, Wang Songlin, Wang Fu
School of Stomatology, Dalian Medical University, Dalian, China.
Dalian Key Laboratory and Academician Laboratory of Immune and Oral Development & Regeneration, Dalian Medical University, Dalian, China.
Alzheimers Res Ther. 2025 Jul 19;17(1):166. doi: 10.1186/s13195-025-01818-3.
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 (IFITM3), 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.
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.
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.
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.
牙周炎是与阿尔茨海默病（AD）相关的危险因素，其特征为β-淀粉样蛋白（Aβ）病理改变。越来越多的证据表明牙周炎在AD的发生和发展中起作用。在小鼠模型中，牙龈卟啉单胞菌（Pg）诱导的牙周炎中I型干扰素上调。在AD患者大脑中已发现Pg的定植。最近，干扰素诱导跨膜蛋白3（IFITM3），一种炎症诱导的固有免疫蛋白，被确定为AD中Aβ产生的新型γ-分泌酶调节蛋白。然而，牙周炎是否会引发大脑中I型干扰素增加，随后通过引发神经胶质细胞的固有免疫反应并激活IFITM3-Aβ轴诱导类似AD的病理改变，仍不清楚。此外，Pg在大脑中的定植是否会诱导星形胶质细胞和小胶质细胞的固有免疫仍未得到解答。
我们使用行为测试评估了Pg诱导的牙周炎对C57BL/6J和APP/PS1小鼠认知障碍的影响。使用定量逆转录聚合酶链反应（qRT-PCR）、蛋白质印迹和组织学染色测量牙周炎/Pg对小胶质细胞和星形胶质细胞的影响。
Pg诱导的牙周炎导致C57BL/6J小鼠认知障碍，并加剧APP/PS1小鼠的认知衰退。此外，Pg诱导的牙周炎提高了C57BL/6J和APP/PS1小鼠大脑中干扰素（IFN）-β、IFITM3和Aβ沉积水平。我们还在Pg诱导的牙周炎模型大脑中鉴定出Pg DNA、神经胶质激活和炎症介质的表达。此外，我们的研究结果证实星形胶质细胞是体外和体内对Pg诱导的固有免疫和炎症的主要反应者。牙周炎还会诱导牙周组织、唾液腺中IFITM3表达增加。
我们确定了牙周炎与认知衰退之间以前未被认识的联系，并提供了新的证据，将口腔致病细菌诱导的固有免疫和神经炎症与AD发病机制和认知衰退联系起来，部分是通过增加血脑屏障（BBB）通透性、引发神经炎症以及神经胶质细胞中IFITM3升高导致Aβ沉积。此外，牙周炎加剧了AD小鼠的固有免疫和认知障碍，强调了针对AD患者牙周疾病的预防和治疗策略的重要性。
