Jiang Muzhou, Ge Ziming, Yin Shoucheng, Liu Yanqing, Gao Hanyu, Lu Lijie, Wang Hongyan, Li Chen, Ni Junjun, Pan Yaping, Lin Li
Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, China.
Key Laboratory of Molecular Medicine and Biotherapy, School of Life Science, Beijing Institute of Technology, Beijing, China.
J Clin Periodontol. 2025 Mar;52(3):434-456. doi: 10.1111/jcpe.14109. Epub 2024 Dec 26.
Porphyromonas gingivalis , a consensus periodontal pathogen, is thought to be involved in Alzheimer's disease (AD) progression, and P. gingivalis -derived outer membrane vesicles (PgOMVs) are a key toxic factor in inducing AD pathology. This study aimed to clarify the regulatory mechanism underlying the PgOMV-induced AD-like phenotype.
We intraperitoneally injected PgOMVs into the periphery of wild-type and CatB knockout mice for 4 or 8 weeks to assess the effect of CatB on PgOMV-induced AD pathology. Mice were evaluated for cognitive change, tau phosphorylation, microglial activation, neuroinflammation and synapse loss. Microglial and primary neuron culture were prepared to verify the in vivo results.
CatB deficiency significantly alleviated PgOMV-induced cognitive dysfunction, microglia-mediated neuroinflammation, tau hyperphosphorylation and synapse loss. Subsequent transcriptomic analysis, immunofluorescence and immunoblotting suggested that CatB modulates microglia-mediated neuroinflammation through stress-activated protein kinases (SAPK)/Jun amino-terminal kinases (JNK) signals after administration of PgOMVs, which in turn regulates neuronal tau phosphorylation and synapse loss in a SAPK/JNK-dependent manner.
Our study unveils a previously unknown role of CatB in regulating PgOMV-induced AD pathology.
牙龈卟啉单胞菌是一种公认的牙周病原体，被认为与阿尔茨海默病（AD）的进展有关，而牙龈卟啉单胞菌衍生的外膜囊泡（PgOMV）是诱导AD病理的关键毒性因子。本研究旨在阐明PgOMV诱导的AD样表型的调控机制。
我们将PgOMV腹腔注射到野生型和组织蛋白酶B（CatB）基因敲除小鼠的外周，持续4周或8周，以评估CatB对PgOMV诱导的AD病理的影响。对小鼠的认知变化、tau蛋白磷酸化、小胶质细胞活化、神经炎症和突触丧失进行评估。制备小胶质细胞和原代神经元培养物以验证体内实验结果。
CatB缺陷显著减轻了PgOMV诱导的认知功能障碍、小胶质细胞介导的神经炎症、tau蛋白过度磷酸化和突触丧失。随后的转录组分析、免疫荧光和免疫印迹表明，在给予PgOMV后，CatB通过应激激活蛋白激酶（SAPK）/Jun氨基末端激酶（JNK）信号调节小胶质细胞介导的神经炎症，进而以SAPK/JNK依赖的方式调节神经元tau蛋白磷酸化和突触丧失。
我们的研究揭示了CatB在调节PgOMV诱导的AD病理中的一个此前未知的作用。
