IL-1 beta and TNF-alpha play an essential role in modulating the risk of both periodontitis and Alzheimer's disease

BACKGROUND: Periodontitis, a chronic systemic inflammatory disease, is a common health problem in the elderly. With increasing recognition that inflammation plays a key role in the pathophysiology of Alzheimer's disease (AD), our research team has been studying how systemic inflammation affects the brain immune responses. Aging is a major risk factor for both periodontitis and AD. As aging causes dysregulation of immune responses, we aimed to define the roles of cytokines in the pathogenesis of periodontitis and AD. METHODS: To induce experimental periodontitis, female WT mice were injected with heat-killed P. gingivalis into their buccal mucosa three times per week every other week for a total of 5 weeks. Another group of mice were injected with IL-1b and TNF-a following the same timeline as above. Sickness Behavior and cognitive functions were assessed through open field and puzzle box test. Mandibular jaws were harvested for Micro-CT scan. Different brain regions were harvested for biochemical analysis. RESULTS: Mice injected with heat-killed bacteria had worsened long-term memory functions. It also significantly increased periodontal bone loss, which was accompanied by increased gene expression levels of IL-1b and TNF-a in the gums. Significant elevated levels of pro-inflammatory cytokines in the liver as well as different brain regions were also observed. Immunostaining revealed increased levels of phospho-tau in WT mice injected with heat-killed bacteria, suggesting that elevated systemic cytokine levels caused by the injection of heat-killed bacteria can lead to the appearance of AD pathology. Another group of mice injected with IL-1b and TNF-a displayed hyperactivity and worsened short-term memory functions. Injections of cytokines also induced periodontal bone loss, which was accompanied by elevated levels of inflammatory cytokines in the liver as well as different brain regions. CONCLUSION: Taken together, our study revealed that increased cytokine immune response in the gums led to periodontal bone loss, brain inflammation and modulated the cognitive functions of WT mice. This research demonstrated that cytokines play a crucial role in the pathogenesis of both periodontitis and AD. Acknowledgement: The study is supported by Health and Medical Research Fund (HMRF 04151216) to RCCC. RPHW is awarded by Hong Kong PhD Fellowship.