Hyperphosphorylated tau is the main component of neurofibrillary tangles and involved in the pathogenesis of Alzheimer’s disease (AD). Increasing evidences suggest close associations between Porphyromonas gingivalis (P. gingivalis) and AD, but the relationship between P. gingivalis and tau hyperphosphorylation is still unclear. In this study, we investigated whether peripheral infection with P. gingivalis caused tau hyperphosphorylation by using wild Sprague-Dawley (SD) rats and HT-22 cells. The rats were injected with P. gingivalis suspension or phosphate-buffered saline 3 times per week. After 4 weeks or 12 weeks, the rats were sacrificed for analyzing systemic inflammation, neuroinflammation, and tau hyperphosphorylation. The results showed that the severity of phosphorylated tau at the AD-related sites Thr181 and Thr231 and the number of activated astrocytes were notably greater in the hippocampus of rats with P. gingivalis injection. And the levels of the inflammatory cytokines interleukin (IL)-1β and IL-6 and tumor necrosis factor-α in serum and hippocampus were also increased in the rats with P. gingivalis injection. In addition, the activity of protein phosphatase 2A (PP2A) was significantly inhibited in the hippocampus of rats with P. gingivalis injection. In vitro, IL-1β induced tau hyperphosphorylation by inhibiting the activity of PP2A in HT-22 cells and application of the PP2A promoter efficiently attenuated IL-1β-induced tau hyperphosphorylation in HT-22 cells. These results indicated that P. gingivalis could induce tau hyperphosphorylation via, in part, attenuating the activity of PP2A through triggering systemic inflammation and neuroinflammation in wild-type SD rats.

过度磷酸化的 tau 是神经原纤维缠结的主要成分，参与阿尔茨海默病 (AD) 的发病机制。越来越多的证据表明牙龈卟啉单胞菌( P. gingivalis ) 与 AD之间存在密切关联，但牙龈卟啉单胞菌与 tau 过度磷酸化之间的关系仍不清楚。在这项研究中，我们通过使用野生 Sprague-Dawley (SD) 大鼠和 HT-22 细胞研究了牙龈卟啉单胞菌的外周感染是否导致 tau 过度磷酸化。给大鼠注射牙龈卟啉单胞菌悬浮液或磷酸盐缓冲盐水每周 3 次。4 周或 12 周后，处死大鼠以分析全身炎症、神经炎症和 tau 过度磷酸化。结果表明，注射牙龈卟啉单胞菌的大鼠海马AD相关位点Thr181和Thr231磷酸化tau的严重程度和活化的星形胶质细胞数量明显增加。牙龈卟啉单胞菌注射液大鼠血清和海马中炎性细胞因子白细胞介素（IL）-1β和IL-6以及肿瘤坏死因子-α的水平也升高。此外，牙龈卟啉单胞菌大鼠海马中蛋白磷酸酶2A（PP2A）的活性受到显着抑制注射。在体外，IL-1β 通过抑制 HT-22 细胞中 PP2A 的活性诱导 tau 过度磷酸化，并且应用 PP2A 启动子有效减弱了 IL-1β 诱导的 HT-22 细胞中的 tau 过度磷酸化。这些结果表明，牙龈卟啉单胞菌可以通过触发野生型 SD 大鼠的全身炎症和神经炎症来部分减弱 PP2A 的活性，从而诱导 tau 过度磷酸化。