Jiang Yiting, Xu Lina, Zhao Xuri, Shen Hui, Qiu Che, He Zhiyan, Song Zhongchen, Zhou Wei
Department of Periodontology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
Front Cell Infect Microbiol. 2025 Jun 9;15:1559182. doi: 10.3389/fcimb.2025.1559182. eCollection 2025.
In our previous study, ()-induced periodontitis caused cognitive impairment which was associated with abnormal amyloid β (Aβ) metabolite in the brain. The brain barrier is critical in maintaining homeostasis, controlling influx and efflux transport and regulating waste clearance. However, the specific role of the brain barrier in linking periodontitis to cognitive function remains unclear.
A murine model of periodontitis-induced cognitive impairment was constructed via oral topical application of Neuroinflammation was observed by detecting the expression of proinflammatory cytokines and glia activation. Western blot (WB), immunohistochemistry (IHC) and immunofluorescence (IF) were used to detect the expression of tau-related molecules and neuronal loss. WB, Evans blue staining and flow cytometry were used to evaluate the blood-brain barrier (BBB) function including the infiltration of and immune cells, and BBB permeability. The changes of meningeal lymphatic drainage were observed using an in vivo animal imaging system and reverse transcription polymerase chain reaction (RT-PCR). The effect of on lymphatic endothelial cells (LECs) was further verified using IF and RT-PCR.
-induced periodontitis exacerbated cognitive impairment by the upregulation of proinflammatory cytokine and glia activation. In the brain of periodontitis mice, p-Akt and p-GSK3β levels were reduced, leading to tau hyperphosphorylation and neuronal loss including cell bodies and neurites. -induced periodontitis enhanced BBB permeability, promoted P. gingivalis and immune cell infiltration, and downregulated the expression of Occludin and ZO-1. In addition, the meningeal lymphatic drainage was impaired and the mRNA levels of lymphangiogenesis-related factor LYVE1 were decreased in the dura matter of periodontitis mice. After infection, the inflammatory response was increased, and LYVE1 and ZO1 expression was decreased in LECs.
Periodontitis aggravated neuroinflammation and neuronal loss which was associated with tau hyperphosphorylation. The impaired meningeal lymphatic vessels (MLV) and disrupted BBB affected the brain barrier function, further inhibiting the clearance of pathogenic substances and enhancing immune cell infiltration in periodontitis mice. These results indicated that brain barrier dysfunction may be the link between periodontitis and cognitive impairment.
在我们之前的研究中，（）诱导的牙周炎导致认知障碍，这与大脑中异常的淀粉样β（Aβ）代谢产物有关。脑屏障在维持体内平衡、控制物质的流入和流出运输以及调节废物清除方面至关重要。然而，脑屏障在将牙周炎与认知功能联系起来方面的具体作用仍不清楚。
通过口腔局部应用构建牙周炎诱导的认知障碍小鼠模型。通过检测促炎细胞因子的表达和胶质细胞激活来观察神经炎症。采用蛋白质免疫印迹法（WB）、免疫组织化学法（IHC）和免疫荧光法（IF）检测tau相关分子的表达和神经元丢失情况。采用WB、伊文思蓝染色和流式细胞术评估血脑屏障（BBB）功能，包括细菌和免疫细胞的浸润以及BBB通透性。使用体内动物成像系统和逆转录聚合酶链反应（RT-PCR）观察脑膜淋巴引流的变化。使用IF和RT-PCR进一步验证细菌对淋巴管内皮细胞（LECs）的影响。
（）诱导的牙周炎通过促炎细胞因子的上调和胶质细胞激活加剧了认知障碍。在牙周炎小鼠的大脑中，p-Akt和p-GSK3β水平降低，导致tau过度磷酸化以及包括细胞体和神经突的神经元丢失。（）诱导的牙周炎增强了BBB通透性，促进了牙龈卟啉单胞菌和免疫细胞浸润，并下调了闭合蛋白和紧密连接蛋白1的表达。此外，牙周炎小鼠硬脑膜中的脑膜淋巴引流受损，淋巴管生成相关因子LYVE1的mRNA水平降低。细菌感染后，LECs中的炎症反应增加，LYVE1和ZO1表达降低。
牙周炎加剧了神经炎症和与tau过度磷酸化相关的神经元丢失。受损的脑膜淋巴管（MLV）和破坏的BBB影响了脑屏障功能，进一步抑制了牙周炎小鼠中致病物质的清除并增强了免疫细胞浸润。这些结果表明脑屏障功能障碍可能是牙周炎与认知障碍之间的联系。
