STAT3 signaling pathway could be involved in the progress of cognitive dysfunction caused by ligature-induced periodontitis

Background: Increasing evidence suggests a causal link between periodontitis and Alzheimer’s disease (AD). Systemic inflammation initiated by periodontitis may mediate the development of AD. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of STAT3 in this process.Materials and Methods: Ligature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS, 5 mg/kg). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography (micro-CT) analysis and histopathological evaluation. The expression of cytokines (IL-1β, IL-6, IL-8, IL-21) in the periphery was evaluated by RT-PCR and ELISA. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes was assessed by immunohistochemistry. In the cortex, the cytokines mentioned above were also detected, while the activation of the STAT3 signalling pathway (JAK2, STAT3, and pSTAT3) was assessed by Western blotting. The expression of amyloid precursor protein (APP) and its key secretase enzymes was evaluated by RT-PCR, while the total Aβ and the ratio of Aβ1-40/1-42 were measured via ELISA.Results: In periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8 and IL-21) were detected; this change was relieved by the pSTAT3 inhibitor CTS. Additionally, spatial learning and memory function was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus. In the cortex, these inflammatory cytokines showed similar changes when the STAT3 signalling pathway was activated. The processing of APP by β- and γ-secretases was promoted, and both the total Aβ and the ratio of Aβ1-40/1-42 were upregulated. Changes in the brain were also attenuated by CTS.Conclusions: Ligature-induced periodontitis in rats resulted in systemic inflammation and further impairments in cognitive function, leading to AD-like pathology. The activation of the STAT3 signalling pathway may play an important role in this process by increasing inflammatory load in both the periphery and brain, promoting neuroinflammation and modulating APP processing. This study may provide novel insights into periodontal intervention strategies and potential targets for AD prevention.