Qiu Yu, Zhao Yueyang, He Guiqiong, Yang Deqin
Chongqing Key Laboratory of Oral Diseases, Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Stomatological Hospital of Chongqing Medical University, Chongqing, China.
Department of Conservative Dentistry and Endodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
Immun Inflamm Dis. 2025 Feb;13(2):e70135. doi: 10.1002/iid3.70135.
Alzheimer's disease (AD) is the most common chronic neurodegenerative disorder, with neuroinflammation playing an important role in its progression to become a major research focus. The role of Porphyromonas gingivalis (Pg) and its outer membrane vesicles (Pg OMVs) in AD development is uncertain, particularly regarding their effects on neuroinflammation.
The cognition of mice injected with Pg, Pg OMVs, or PBS via the tail vein was assessed by the Morris water maze test. Pathological changes in the mouse brain were analyzed via immunohistochemistry, immunofluorescence and hematoxylin‒eosin (H&E) staining, and the ultrastructure of the hippocampus was observed via transmission electron microscopy (TEM). Plasma levels of inflammatory factors were assessed by enzyme-linked immunosorbent assay (ELISA). Protein levels of brain inflammatory factor, occludin, and NLRP3 inflammasome-related proteins were assessed by western blotting.
Memory impairment; notable neuroinflammation, including astrocyte and microglial activation; and elevated protein levels of IL-1β, TNF-α, and IL-6 in the hippocampus were detected in the Pg and Pg OMV groups. However, Pg induced weight loss and systemic inflammation, such as splenomegaly and increased IL-1β and TNF-α levels in plasma, whereas Pg OMVs had minimal impact. In addition, Pg induced more pronounced activation of the NLRP3 inflammasome compared to Pg OMVs. In contrast, only the Pg OMV group exhibited blood-brain barrier (BBB) disruption characterized by reduced integrity of tight junctions and lower levels of occludin protein.
Pg is associated with a significant immune response and systemic inflammation, which in turn exacerbates neuroinflammation via activating NLRP3 inflammasome. However, Pg OMVs might elude the systemic immune response and disrupt tight junctions, thereby entering the brain and directly triggering neuroinflammation.
阿尔茨海默病（AD）是最常见的慢性神经退行性疾病，神经炎症在其进展过程中起重要作用，已成为主要研究焦点。牙龈卟啉单胞菌（Pg）及其外膜囊泡（Pg OMVs）在AD发展中的作用尚不确定，尤其是它们对神经炎症的影响。
通过莫里斯水迷宫试验评估经尾静脉注射Pg、Pg OMVs或磷酸盐缓冲液（PBS）的小鼠的认知情况。通过免疫组织化学、免疫荧光和苏木精-伊红（H&E）染色分析小鼠脑内的病理变化，并通过透射电子显微镜（TEM）观察海马体的超微结构。通过酶联免疫吸附测定（ELISA）评估血浆中炎症因子的水平。通过蛋白质免疫印迹法评估脑内炎症因子、闭合蛋白和NLRP3炎性小体相关蛋白的水平。
在Pg组和Pg OMVs组中均检测到记忆障碍；显著的神经炎症，包括星形胶质细胞和小胶质细胞活化；以及海马体中白细胞介素-1β（IL-1β）、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的蛋白质水平升高。然而，Pg会导致体重减轻和全身炎症，如脾肿大以及血浆中IL-1β和TNF-α水平升高，而Pg OMVs的影响极小。此外，与Pg OMVs相比，Pg诱导NLRP3炎性小体的激活更为明显。相比之下，只有Pg OMVs组表现出血脑屏障（BBB）破坏，其特征为紧密连接完整性降低和闭合蛋白水平降低。
Pg与显著的免疫反应和全身炎症相关，进而通过激活NLRP3炎性小体加剧神经炎症。然而，Pg OMVs可能避开全身免疫反应并破坏紧密连接，从而进入大脑并直接引发神经炎症。
